Pyrazolo-pyridine derivatives as antiherpes agents

ABSTRACT

The present invention provides compounds of formula (I):  
                 
 
     wherein all variables are as defined herein, pharmaceutical compositions containing the same, processes for preparing the same and their use as pharmaceutical agents.

BACKGROUND OF THE INVENTION

[0001] The present invention relates to novel compounds, pharmaceuticalformulations comprising these compounds, and the use of these compoundsin therapy. More particularly, the present invention relates tocompounds for the prophylaxis and treatment of herpes viral infections.

[0002] Of the DNA viruses, those of the herpes group are the sources ofthe most common viral illnesses in man. The group includes herpessimplex virus types 1 and 2 (HSV), varicella zoster virus (VZV),cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpes virus type6 (HHV-6), human herpes virus type 7 (HHV-7) and human herpes virus type8 (HHV-8). HSV-1 and HSV-2 are some of the most common infectious agentsof man. Most of these viruses are able to persist in the host's neuralcells; once infected, individuals are at risk of recurrent clinicalmanifestations of infection which can be both physically andpsychologically distressing.

[0003] Herpes simplex viruses (HSV-1 and -2) are the causative agents ofherpes labialis and genital herpes. HSV infection is often characterisedby extensive and debilitating lesions of the skin, mouth and/orgenitals. Primary infections may be subclinical although tend to be moresevere than infections in individuals previously exposed to the virus.Ocular infection by HSV can lead to keratitis or cataracts therebyendangering the host's sight. Infection in the new-born, inimmunocompromised patients or penetration of the infection into thecentral nervous system can prove fatal. In the US alone, 40 millionindividuals are infected with HSV-2, a number that is expected toincrease to 60 million by 2007. Over 80% of individuals infected withHSV-2 are unaware they carry and spread the virus, and of thosediagnosed less than 20% received oral therapies. The net result is thatless than 5% of the infected population are treated. Likewise of the 530million individuals worldwide who carry the HSV-1 virus, 81% of thesymptomatic population remain untreated. No cure exists for HSVinfection, and once infected, individuals carry the virus for life in adormant state. Reactivation of the virus from latency occursperiodically and may be triggered by stress, environmental factors,and/or suppression of the host immune system. Currently, the use ofnucleoside analogs such as valaciclovir (VALTREX®) and aciclovir(ZOVIRAX®) is the standard of care for managing genital herpes virusoutbreaks.

[0004] VZV is a herpes virus which causes chickenpox and shingles.Chickenpox is the primary disease produced in a host without immunity,and in young children is usually a mild illness characterised by avesicular rash and fever. Shingles or zoster is the recurrent form ofthe disease which occurs in adults who were previously infected withVZV. The clinical manifestations of shingles are characterised byneuralgia and a vesicular skin rash that is unilateral and dermatomal indistribution. Spread of inflammation may lead to paralysis orconvulsions. Coma can occur if the meninges become affected. VZV is ofserious concern in patients receiving immunosuppressive drugs fortransplant purposes or for treatment of malignant neoplasia and is aserious complication of AIDS patients due to their impaired immunesystem.

[0005] In common with other herpes viruses, infection with CMV leads toa lifelong association of virus and host Congenital infection followinginfection of the mother during pregnancy may give rise to clinicaleffects such as death or gross disease (microcephaly,hepatosplenomegaly, jaundice, mental retardation), retinitis leading toblindness or, in less severe forms, failure to thrive, andsusceptibility to chest and ear infections. CMV infection in patientswho are immunocompromised for example as a result of malignancy,treatment with immunosuppressive drugs following transplantation orinfection with Human Immunodeficiency Virus, may give rise to retinitis,pneumonitis, gastrointestinal disorders and neurological diseases. CMVinfection is also associated with cardiovascular diseases and conditionsincluding restenosis and atherosclerosis.

[0006] The main disease caused by EBV is acute or chronic infectiousmononucleosis (glandular fever). Examples of other EBV or EBV associateddiseases include lymphoproliferative disease which frequently occurs inpersons with congenital or acquired cellular immune deficiency, X-linkedlymphoproliferative disease which occurs namely in young boys,EBV-associated B-cell tumours, Hodgkin's disease, nasopharyngealcarcinoma, Burkitt lymphoma, non-Hodgkin's lymphoma, thymomas and oralhairy leukoplakia. EBV infections have also been found in associationwith a variety of epithelial-cell-derived tumours of the upper and lowerrespiratory tracts including the lung. EBV infection has also beenassociated with other diseases and conditions including chronic fatiguesyndrome and multiple sclerosis.

[0007] HHV-6 has been shown to be a causative agent of infantum subitumin children and of kidney rejection and interstitial pneumonia in kidneyand bone marrow transplant patients, respectively, and may be associatedwith other diseases such as multiple sclerosis. There is also evidenceof repression of stem cell counts in bone marrow transplant patients.HHV-7 is of undetermined disease aetiology.

[0008] Hepatitis B virus (HBV) is a viral pathogen of world-wide majorimportance. The virus is aetiologically associated with primaryhepatocellular carcinoma and is thought to cause 80% of the world'sliver cancer. Clinical effects of infection with HBV range fromheadache, fever, malaise, nausea, vomiting, anorexia and abdominalpains. Replication of the virus is usually controlled by the immuneresponse, with a course of recovery lasting weeks or months in humans,but infection may be more severe leading to persistent chronic liverdisease outlined above.

[0009] U.S. Pat. No. 5,498,774 and European Patent No. 0 404 190 toMitsudera et al., relates to condensed heterocyclic compounds of thegeneral formula (I):

[0010] wherein Q is a condensed heterocyclic group having a nitrogenatom in the bridgehead which is unsubstituted or substituted, X is ahydrogen atom or a group attached through C, O, S or N, and Y is anelectron attractive group; or its salt which is useful as anagricultural chemical.

BRIEF SUMMARY OF THE INVENTION

[0011] According to a first aspect of the invention there is provided acompound of formula (I):

[0012] wherein:

[0013] p is 0, 1, 2, 3 or 4;

[0014] each R¹ is the same or different and is independently selectedfrom the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OR¹⁰Ay, —OHet, —OR¹⁰Het, —C(O)R⁹,—C(O)Ay, —C(O)Het, —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(O)NHR¹⁰Ay,—C(O)NHR¹⁰Het, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —S(O)_(n)R⁹,—S(O)_(n)Ay, —S(O)_(n)Het, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —NR⁷R⁸, —NR⁷Ay,—NHHet, —NHR¹⁰Ay, —NHR¹⁰Het, —R¹⁰cycloalkyl, —R¹⁰Ay, —R¹⁰Het,—R¹⁰O—C(O)R⁹, —R¹⁰O—C(O)Ay, —R¹⁰O—C(O)Het, —R¹⁰O—S(O)_(n)R⁹, —R¹⁰OR⁹,—R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(O)NR⁷Ay, —R¹⁰C(O)NHR¹⁰Het,—R¹⁰C(S)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹, —R¹⁰SO₂NR⁹R¹¹,—R¹⁰SO₂NHCOR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰NHC(NH)NR⁹R¹¹, cyano, nitro andazido;

[0015] or two adjacent R¹ groups together with the carbon atoms to whichthey are bonded form a cycloalkyl or a 5- or 6-membered heterocyclicgroup containing 1 or 2 heteroatoms;

[0016] each R⁷ and R⁸ are the same or different and are independentlyselected from the group consisting of H, alkyl, alkenyl, cycloalkyl,cycloalkenyl, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁹R¹¹, —C(S)NR⁹R¹¹, —C(NH)NR⁹R¹¹,—SO₂R¹⁰, —SO₂NR⁹R¹¹, —R¹⁰cycloalkyl, —R¹⁰OR⁹, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹,—R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R¹⁰,—R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂NHCOR⁹, —R¹⁰NR⁹R¹¹, —R¹⁰NHCOR⁹, —R¹⁰NHSO₂R⁹ and—R¹⁰NHC(NH)NR⁹R¹¹;

[0017] each R⁹ and R¹¹ are the same or different and are independentlyselected from the group consisting of H, alkyl, cycloalkyl,—R¹⁰cycloalkyl, —R¹⁰OH, —R¹⁰(OR¹⁰)_(w) wherein w is 1-10, and—R¹⁰NR¹⁰R¹⁰;

[0018] each R¹⁰ is the same or different and is independently selectedfrom the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl andcycloalkenyl;

[0019] Ay is aryl;

[0020] Het is a 5- or 6-membered heterocyclic or heteroaryl group;

[0021] Y is N or CH;

[0022] R² is selected from the group consisting of halo, alkyl, alkenyl,cycloalkyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Het,—S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸, —NHHet,—NHR¹⁰Ay, —NHR¹⁰Het, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay;

[0023] n is 0, 1 or 2;

[0024] R³ and R⁴ are the same or different and are each independentlyselected from the group consisting of H, halo, alkyl, alkenyl,cycloalkyl, Ay, Het, —OR⁷, —OAy, —C(O)R⁷, C(O)Ay, —CO₂R⁷, —CO₂Ay,—SO₂NHR⁹, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Het, —R¹⁰cycloalkyl, —R¹⁰OR⁷,—R¹⁰OAy, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay;

[0025] Ring A is a 5-10 membered heterocyclic or heteroaryl group;

[0026] q is 0, 1, 2, 3, 4 or 5; and

[0027] each R⁵ is the same or different and is independently selectedfrom the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OR¹⁰Ay, —OHet, —OR¹⁰Het, —C(O)R⁹,—C(O)Ay, —C(O)Het, —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(O)NHR¹⁰Het,—C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —S(O)_(n)R⁹, —S(O)₂NR⁷R⁸,—S(O)₂NR⁷Ay, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay, —NHR¹⁰Het,—R¹⁰cycloalkyl, —R¹⁰Het, —R¹⁰OR⁹, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹,—R¹⁰C(O)NR⁷Ay, —R¹⁰C(O)NHR¹⁰Het, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹,—R¹⁰SO₂R⁹, —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂NHCOR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay,—R¹⁰NHC(NH)NR⁹R¹¹, cyano, nitro and azido;

[0028] wherein when Y is CH, R³ is not —NR⁷Ay;

[0029] or a pharmaceutically acceptable salt, solvate or physiologicallyfunctional derivative thereof.

[0030] According to a second aspect, the present invention provides apharmaceutical composition comprising a compound of formula (I). Thepharmaceutical composition may further comprise a pharmaceuticallyacceptable carrier or diluent. The pharmaceutical composition mayfurther comprise an antiviral agent In one embodiment, thepharmaceutical composition further comprises an antiviral agent selectedfrom the group consisting of aciclovir and valaciclovir.

[0031] According to a third aspect, the present invention provides amethod for the prophylaxis or treatment of a herpes viral infection inan animal. The method comprises administering to the animal atherapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt, solvate or physiologically functionalderivative thereof. The herpes viral infection may be selected from thegroup consisting of herpes simplex virus 1, herpes simplex virus 2,cytomegalovirus, Epstein Barr Virus, herpes zoster virus, human herpesvirus 6, human herpes virus 7 and human herpes virus 8.

[0032] According to a fourth aspect, the present invention provides amethod for the prophylaxis or treatment of a condition or diseaseassociated with a herpes viral infection in an animal, comprisingadministering to the animal a therapeutically effective amount of acompound of formula (I) or a pharmaceutically acceptable salt, solvateor physiologically functional derivative thereof.

[0033] According to a fifth aspect, the present invention provides aprocess for preparing a compound of formula (I) wherein Y is N and R³and R⁴ are H. The process comprises reacting a compound of formula (IX):

[0034] with a compound of formula (X):

[0035] According to a sixth aspect, the present invention provides aprocess for preparing a compound of formula (I) wherein Y is N; R³ isselected from the group consisting of of H, alkyl, cycloalkyl, alkenyl,Ay, Het, —OR⁷, —OAy, —C(O)R⁷, C(O)Ay, —CO₂R⁷, —CO₂Ay, —SO₂NHR⁹, —NR⁷R⁸(where R⁷ and R⁸ are not H), —NR⁷Ay (where R⁷is not H), —R¹⁰cycloalkyl,—R¹⁰OR⁷, —R¹⁰OAy, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; and R⁴ is H. The processcomprises reacting a compound of formula (XVI):

[0036] with a compound of formula (X):

[0037] According to a seventh aspect, the present invention provides aprocess for preparing a compound of formula (I) wherein Y is N. Theprocess comprises reacting a compound of formula (XX):

[0038] with a compound of formula (X):

[0039] followed by oxidative aromatization.

[0040] According to an eighth aspect, the present invention provides aprocess for preparing a compound of formula (I). The process comprisesreacting a compound of formula (XXII):

[0041] wherein X¹ is chloro, bromo or iodo;

[0042] with a compound of formula (XXIV):

[0043] wherein M₂ is -B(OH)₂, -B(ORa)₂, -B(Ra)₂, —Sn(Ra)₃, Zn-halide,ZnRa, or Mg-halide where Ra is alkyl or cycloalkyl and halide is halo.

[0044] According to a ninth aspect, the present invention provides aprocess for preparing a compound according of formula (I). The processcomprises reacting a compound of formula (XXIX):

[0045] with a 1-aminopyridinium salt of formula (XXX):

[0046] wherein Z- is a counter ion.

[0047] According to a tenth aspect, the present invention provides aprocess for preparing a compound of formula (I). The process comprisesreacting a compound of formula (XXXVI):

[0048] with a suitable ring forming reagent.

[0049] In another aspect, the present invention provides a radiolabeledcompound of formula (I) or a salt, solvate or physiologically functionalderivative thereof. In one embodiment, the present invention provides atritiated compound of formula (I) or a pharmaceutically acceptable salt,solvate or physiologically functional derivative thereof.

[0050] In another aspect, the present invention provides a compound offormula (I) for use in therapy.

[0051] In yet another aspect, the present invention provides a compoundof formula (I) for use in the prophylaxis or treatment of a herpes viralinfection.

[0052] In another aspect, the present invention provides apharmaceutical composition for use in the prophylaxis or treatment of aherpes viral infection in an animal, such as a human, comprising acompound of formula (I).

[0053] In yet another aspect, the present invention provides a compoundof formula (I) for use in the prophylaxis or treatment of a condition ordisease associated with a herpes viral infection in an animal, such as ahuman.

[0054] In yet another aspect, the present invention provides apharmaceutical composition for use in the prophylaxis or treatment of acondition or disease associated with a herpes viral infection in ananimal, comprising a compound of formula (I).

[0055] In yet another aspect, the present invention provides the use ofa compound of formula (I) for the preparation of a medicament for theprophylaxis or treatment of a herpes viral infection in an animal, suchas a human.

[0056] In yet another aspect, the present invention provides the use ofa compound of formula (I) for the preparation of a medicament for theprophylaxis or treatment of a condition or disease associated with aherpes viral infection in an animal, such as a human.

DETAILED DESCRIPTION OF THE INVENTION

[0057] As used herein, “a compound of the invention” or “a compound offormula (I)” means a compound of formula (I) or a pharmaceuticallyacceptable salt, solvate, or physiologically functional derivativethereof. Similarly, with respect to isolatable intermediates such ascompounds of formula (IX), (XVI), (XX), (XXII), (XXIX) and (XXXVI), thephrase “a compound of formula (number)” means a compound having thatformula or a pharmaceutically acceptable salt, solvate orphysiologically functional derivative thereof.

[0058] As used herein, the terms “alkyl” and “alkylene” refer tostraight or branched hydrocarbon chains containing from 1 to 8 carbonatoms. Examples of “alkyl” as used herein include, but are not limitedto, methyl, ethyl, n-propyl, n-butyl, n-pentyl, isobutyl, isopropyl, andtert-butyl. Examples of “alkylene” as used herein include, but are notlimited to, methylene, ethylene, propylene, butylene, and isobutylene.“Alkyl” and “alkylene” also include substituted alkyl and substitutedalkylene. The alkyl or alkylene groups may be optionally substitutedwith one or more substituents selected from the group consisting ofmercapto, nitro, cyano, and halo. Perhaloalkyl, such as trifluoromethylis one particular alkyl group.

[0059] As used herein, the term “cycloalkyl” refers to a non-aromaticcarbocyclic ring having from 3 to 8 carbon atoms (unless otherwisespecified) and no carbon-carbon double bonds. “Cycloalkyl” includes byway of example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and cyclooctyl. “Cycloalkyl” also includes substitutedcycloalkyl. The cycloalkyl may be optionally substituted on anyavailable carbon with one or more substituents selected from the groupconsisting of mercapto, nitro, cyano, halo, and alkyl.

[0060] As used herein, the term “alkenyl” refers to straight or branchedhydrocarbon chains containing from 2 to 8 carbon atoms and at least oneand up to three carbon-carbon double bonds. Examples of “alkenyl” asused herein include, but are not limited to ethenyl and propenyl.“Alkenyl” also includes substituted alkenyl. The alkenyl groups may beoptionally substituted one any available carbon with one or moresubstituents selected from the group consisting of mercapto, nitro,cyano, halo, and alkyl.

[0061] As used herein, the term “cycloalkenyl” refers to a non-aromaticcarbocyclic ring having from 3 to 8 carbon atoms (unless otherwisespecified) and up to 3 carbon-carbon double bonds. “Cycloalkenyl”includes by way of example cyclobutenyl, cyclopentenyl and cyclohexenyl.“Cycloalkenyl” also includes substituted cycloalkenyl. The cycloalkenylmay be optionally substituted on any available carbon with one or moresubstituents selected from the group consisting of mercapto, nitro,cyano, halo, and alkyl.

[0062] As used herein, the term “alkynyl” refers to straight or branchedhydrocarbon chains containing from 2 to 8 carbon atoms and at least oneand up to three carbon-carbon triple bonds. Examples of “alkynyl” asused herein include, but are not limited to ethynyl and propynyl.“Alkynyl” also includes substituted alkynyl. The alkynyl groups may beoptionally substituted on any available carbon with one or moresubstituents selected from the group consisting of mercapto, nitro,cyano, and halo.

[0063] The term “halo” or “halogen” refers to fluorine, chlorine,bromine and iodine.

[0064] The term “aryl” refers to monocyclic carbocyclic groups and fusedbicyclic carbocyclic groups having from 5 to 12 carbon atoms and havingat least one aromatic ring. Examples of particular aryl groups includebut are not limited to phenyl, and naphthyl. “Aryl” also includessubstituted aryl. Aryl rings may be optionally substituted withsubstituents selected from the group consisting of halo, alkyl(including perhaloalkyl, e.g., perfluoroalkyl), alkenyl, cycloalkyl,cycloalkenyl, alkoxy, amino, hydroxy, alkylhydroxy, alkylamine, carboxy,carboxamide, sulfonamide, Het, amidine, cyano, nitro and azido.Preferred aryl groups according to the invention include but are notlimited to phenyl and substituted phenyl.

[0065] The term “heterocyclic” or “heterocycle” refers to monocyclicsaturated or unsaturated non-aromatic groups and fused bicyclicnon-aromatic groups, having the specified number of members (e.g. carbonand heteroatoms N and/or O and/or S) and containing 1, 2, 3 or 4heteroatoms selected from N, O and S. Examples of particularheterocyclic groups include but are not limited to tetrahydrofuran,dihydropyran, tetrahydropyran, pyran, oxetane, thietane, 1,4-dioxane,1,3-dioxane, 1,3-dioxalane, piperidine, piperazine,tetrahydropyrimidine, pyrrolidine, morpholine, thiomorpholine,thiazolidine, oxazolidine, tetrahydrothiopyran, tetrahydrothiophene, andthe like. “Heterocyclic” also includes substituted heterocyclic. Theheterocyclic group may be optionally substituted with substituentsselected from the group consisting of halo, alkyl (includingperhaloalkyl, e.g., perfluoroalkyl), alkenyl, cycloalkyl, cycloalkenyl,perfluoroalkyl, alkoxy, amino, hydroxy, alkylhydroxy, alkylamine,carboxy, carboxamide, sulfonamide, Het, amidine, cyano, nitro and azido.Preferred heterocyclic groups according to the invention include but arenot limited to substituted and unsubstituted tetrahydrofuran,pyrrolidine, piperidine, morpholine, thiomorpholine and piperazine, andsubstituted variants thereof.

[0066] The term “heteroaryl” refers to aromatic monocyclic groups andaromatic fused bicyclic groups having the specified number of members(e.g. carbon and heteroatoms N and/or O and/or S) and containing 1, 2,3, or 4 heteroatoms selected from N, O and S. Examples of particularheteroaryl groups include but are not limited to furan, thiophene,pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole,isoxazole, oxadiazole, thiadiazole, isothiazole, pyridine, pyridazine,pyrazine, pyrimidine, quinoline, isoquinoline, benzofuran,benzothiophene, indole, and indazole. “Heteroaryl” also includessubstituted heteroaryl. The heteroaryl group may be optionallysubstituted with substituents selected from the group consisting ofhalo, alkyl (including perhaloalkyl, e.g., perfluoroalkyl), alkenyl,cycloalkyl, cycloalkenyl, perfluoroalkyl, alkoxy, amino, hydroxy,alkylhydroxy, alkylamine, carboxy, carboxamide, sulfonamide, Het,amidine, cyano, nitro and azido. Preferred heteroaryl groups accordingto the invention include but are not limited to substituted andunsubstituted pyridine, furan, thiophene, pyrrole, imidazole, pyrazole,oxazole, thiazole and pyrimidine, and substituted variants thereof.

[0067] The term “members” (and variants thereof e.g., “membered”) in thecontext of heterocyclic and heteoraryl groups refers to the total atoms,carbon and heteroatoms N, O and/or S, which form the ring. Thus, anexample of a 6-membered heterocyclic ring is piperidine and an exampleof a 6-membered heteroaryl ring is pyridine.

[0068] As used herein, the term “optionally” means that the subsequentlydescribed event(s) may or may not occur, and includes both event(s) thatoccur and events that do not occur.

[0069] The present invention provides compounds of formula (I):

[0070] wherein:

[0071] p is 0, 1, 2, 3 or 4;

[0072] each R¹ is the same or different and is independently selectedfrom the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OR¹⁰Ay, —OHet, —OR¹⁰Het, —C(O)R⁹,—C(O)Ay, —C(O)Het, —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(O)NHR¹⁰Ay,—C(O)NHR¹⁰Het, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —S(O)_(n)R⁹,—S(O)_(n)Ay, —S(O)_(n)Het, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —NR⁷R⁸, —NR⁷Ay,—NHHet, —NHR¹⁰Ay, —NHR¹⁰Het, —R¹⁰cycloalkyl, —R¹⁰Ay, —R¹⁰Het,—R¹⁰O—C(O)R⁹, —R¹⁰O—C(O)Ay, —R¹⁰O—C(O)Het, —R¹⁰O—S(O)_(n)R⁹, —R¹⁰OR⁹,—R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(O)NR⁷Ay, —R¹⁰C(O)NHR¹⁰Het,—R¹⁰C(S)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹, —R¹⁰SO₂NR⁹R¹¹,—R¹⁰SO₂NHCOR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰NHC(NH)NR⁹R¹¹, cyano, nitro andazido;

[0073] or two adjacent R¹ groups together with the carbon atoms to whichthey are bonded form a cycloalkyl or a 5- or 6-membered heterocyclicgroup containing 1 or 2 heteroatoms;

[0074] each R⁷ and R⁸ are the same or different and are independentlyselected from the group consisting of H, alkyl, alkenyl, cycloalkyl,cycloalkenyl, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁹R¹¹, —C(S)NR⁹R¹¹, —C(NH)NR⁹R¹¹,—SO₂R¹⁰, —SO₂NR⁹R¹¹, —R¹⁰cycloalkyl, —R¹⁰OR⁹, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹,—R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R¹⁰,—R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂NHCOR⁹, —R¹⁰NR⁹R¹¹, —R¹⁰NHCOR⁹, —R¹⁰NHSO₂R⁹ and—R¹⁰NHC(NH)NR⁹R¹¹;

[0075] each R⁹ and R¹¹ are the same or different and are independentlyselected from the group consisting of H, alkyl, cycloalkyl,—R¹⁰cycloalkyl, —R¹⁰OH, —R¹⁰(OR¹⁰)_(w) wherein w is 1-10, and—R¹⁰NR¹⁰R¹⁰;

[0076] each R¹⁰ is the same or different and is independently selectedfrom the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl andcycloalkenyl;

[0077] Ay is aryl;

[0078] Het is a 5- or 6-membered heterocyclic or heteroaryl group;

[0079] Y is N or CH;

[0080] R² is selected from the group consisting of halo, alkyl, alkenyl,cycloalkyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Het,—S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸, —NHHet,—NHR¹⁰Ay, —NHR¹⁰Het, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay;

[0081] n is 0, 1 or 2;

[0082] R³ and R⁴ are the same or different and are each independentlyselected from the group consisting of H, halo, alkyl, alkenyl,cycloalkyl, Ay, Het, —OR⁷, —OAy, —C(O)R, C(O)Ay, —CO₂R⁷, —CO₂Ay,—SO₂NHR⁹, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Het, —R¹⁰cycloalkyl, —R¹⁰OR⁷,—R¹⁰OAy, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay;

[0083] Ring A is a 5-10 membered heterocyclic or heteroaryl group;

[0084] q is 0, 1, 2, 3, 4 or 5; and

[0085] each R⁵ is the same or different and is independently selectedfrom the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OR¹⁰Ay, —OHet, —OR¹⁰Het, —C(O)R⁹,—C(O)Ay, —C(O)Het, —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(O)NHR¹⁰Het,—C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —S(O)_(n)R⁹, —S(O)₂NR⁷R⁸,—S(O)₂NR⁷Ay, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay, —NHR¹⁰Het,—R¹⁰cycloalkyl, —R¹⁰Het, —R¹⁰OR⁹, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹,—R¹⁰C(O)NR⁷Ay, —R¹⁰C(O)NHR¹⁰Het, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹,—R¹⁰SO₂R⁹, —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂NHCOR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay,—R¹⁰NHC(NH)NR⁹R¹¹, cyano, nitro and azido;

[0086] wherein when Y is CH, R³ is not —NR⁷Ay;

[0087] or a pharmaceutically acceptable salt, solvate or physiologicallyfunctional derivative thereof.

[0088] In one embodiment, the compounds of formula (I) are definedwherein p is 0, 1 or 2. More particularly, p is 1 or 2. In oneembodiment of the present invention, the compounds of formula (I) aredefined wherein p is 1. In one embodiment of the present invention, thecompounds of formula (I) are defined wherein p is 2.

[0089] R¹ may be located at any of the C-4, C-5, C-6 and/or C-7positions on the pyrazolopyridine ring.

[0090] In one embodiment of the invention wherein p is 1 or more, atleast one R¹ contains an aryl, heterocyclic or heteroaryl moiety (e.g.,at least one R¹ is selected from the group consisting of Ay, Het, —OAy,—OR¹⁰Ay, —OHet, —OR¹⁰Het, —C(O)Ay, —C(O)Het, —C(O)NR⁷Ay, —C(O)NHR¹⁰Ay,—C(O)NHR¹⁰Het, —C(NH)NR⁷Ay, —S(O)Ay, —S(O)_(n)Het, —S(O)₂NR⁷Ay, —NR⁷Ay,—NHHet, —NHR¹⁰Ay, —NHR¹⁰Het, —R¹⁰Ay, —R¹⁰Het, —R¹⁰O—C(O)Ay,—R¹⁰O—C(O)Het, —R¹⁰C(O)NR⁷Ay, —R¹⁰C(O)NHR¹⁰Het and —R¹⁰NR⁷Ay, or anysubset thereof). In another embodiment, compounds of formula (I) aredefined wherein at least one R¹ contains a heterocyclic or heteroarylmoiety (e.g., at least one R¹ is selected from the group consisting ofHet, —OHet, —OR¹⁰Het, —C(O)Het, —C(O)NHR¹⁰Het, —S(O)_(n)Het, —NHHet,—NHR¹⁰Het, —R¹⁰Het, —R¹⁰O—C(O)Het and —R¹⁰C(O)NHR¹⁰Het, or any subsetthereof). In yet another embodiment, the compounds of formula (I) aredefined wherein no R¹ contains an aryl, heterocyclic or heteroarylmoiety (e.g., each R¹ is the same or different and is independentlyselected from the group consisting of halo, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, —OR⁷, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁷R⁸,—C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —S(O)_(n)R⁹, —S(O)₂NR⁷R⁸, —NR⁷R⁸,—R¹⁰cycloalkyl, —R¹⁰O—C(O)R⁹, —R¹⁰O—S(O)_(n)R⁹, —R¹⁰OR⁹, —R¹⁰C(O)R⁹,—R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹,—R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂NHCOR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NHC(NH)NR⁹R¹¹, cyano, nitroand azido; or any subset thereof). In another embodiment, no R¹ containsa heteroaryl or heterocyclic moiety but may contain an aryl moiety(e.g., each R¹ is the same or different and is independently selectedfrom the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, Ay, —OR⁷, —OAy, —OR¹⁰Ay, —C(O)R⁹, —C(O)Ay, —CO₂R⁹,—C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(O)NHR¹⁰Ay, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸,—C(NH)NR⁷Ay, —S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —NR⁷R⁸,NR⁷Ay, —NHR¹⁰Ay, —R¹cycloalkyl, —R¹⁰Ay, —R¹⁰O—C(O)R⁹, —R¹⁰O—C(O)Ay,—R¹⁰O—S(O)_(n)R⁹, —R¹⁰OR⁹, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹,—R¹⁰C(O)NR⁷Ay, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹,—R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂NHCOR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰NHC(NH)NR⁹R¹¹,cyano, nitro and azido, or any subset thereof).

[0091] One class of compounds of formula (I) includes those compoundsdefined wherein two adjacent R¹ groups together with the carbon atoms towhich they are bonded form a cycloalkyl or a 5- or 6-memberedheterocyclic group containing 1 or 2 heteroatoms. By “two adjacent R¹groups” is meant that two R¹ groups are bonded to adjacent carbon atoms.When two adjacent R¹ groups together with the carbon atoms to which theyare bonded form a cycloalkyl or a 5- or 6-membered heterocyclic grouphaving 1 or 2 heteroatoms, each R¹ group may be the same or differentand is selected from the group consisting of alkyl, —OR⁷, —NR⁷R⁸, and—S(O)_(n)R⁹. For example, in one embodiment two adjacent R¹ groups are—OR⁷ and together with the carbon atoms to which they are bonded, theyform a heterocyclic group such as:

[0092] In another embodiment, two adjacent R¹ groups are alkyl andtogether with the carbon atoms to which they are bonded, they form acycloalkyl group such as:

[0093] In another embodiment two adjacent R¹ groups are defined as —OR⁷and —NR⁷R⁸ respectively and together with the carbon atoms to which theyare bonded, they form a heterocyclic group such as:

[0094] In another embodiment two adjacent R¹ groups are defined as—S(O)_(n)R⁹ and —NR⁷R⁸ respectively and together with the carbon atomsto which they are bonded, they form a heterocyclic group such as:

[0095] From these examples, additional embodiments can be readilyascertained by those skilled in the art.

[0096] In one particular embodiment, two adjacent R¹ groups togetherwith the carbon atoms to which they are bonded do not form a cycloalkylor a 5- or 6-membered heterocyclic group containing 1 or 2 heteroatoms.

[0097] In one embodiment, each R¹ is the same or different and isindependently selected from the group consisting of halo, alkyl, Ay,Het, —OR⁷, —OAy, —C(O)Het, —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)NR⁷Ay,—C(O)NHR¹⁰Het, —S(O)_(n)R⁹, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay, —NHR¹⁰Het,—R¹⁰OR⁹, cyano, nitro and azido, or any subset thereof. Moreparticularly, each R¹ is the same or different and is independentlyselected from the group consisting of halo, alkyl, Ay, Het, —OR⁷,—C(O)Het, —C(O)NR⁷R⁸, —C(O)NHR¹⁰Het, —S(O)_(n)R⁹, —NR⁷R⁸, —NR⁷Ay,—NHHet, —NHR¹⁰Ay, —NHR¹⁰Het, —R¹⁰OR⁹ and cyano, or any subset thereof.In one particular embodiment wherein p is 1 or more, each R¹ is the sameor different and is independently selected from the group consisting ofhalo, alkyl, Het, —OR⁷, —C(O)NR⁷R⁸, —S(O)_(n)R⁹, —NR⁷R⁸, —NR⁷Ay and—NHHet, or any subset thereof. In one embodiment, R¹ is —NR⁷R⁸.

[0098] More specifically, particular compounds of formula (I) aredefined wherein p is 1 or more and each R¹ is the same or different andis independently selected from the group consisting of halo, alkyl,—NH₂, —NH-alkyl, —NH-cycloalkyl, —N(alkyl)(alkyl), phenyl, Het,—O-alkyl, —N(alkyl)-O-alkyl, —NHAy, —C(O)NH₂, —C(O)NH(alkyl),—C(O)N(alkyl)(alkyl) and —S-alkyl, or any subset thereof. Moreparticularly, R¹ is selected from the group consisting of —NH-alkyl,—NH-cycloalkyl and pyrrolidone, or any subset thereof.

[0099] Specific examples of some particular R¹ groups are selected fromthe group consisting of Cl, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, trifluoromethyl, —NH₂, —NH-methyl, —N(CH₃)₂, —NH-cyclopentyl,—NH-cyclopropyl, —NH-isopropyl, —NH-butyl, —NH-phenyl, —N(CH₂)₂OCH₃,pyrrolidine, methoxy, ethoxy, propoxy, isopropoxy, butoxy, thiomethoxy,thioethoxy, thioisopropoxy, and pyrrolidine, or any subset thereof.

[0100] In one embodiment, R⁷ and R⁸ are each the same or different andare each independently selected from the group consisting of H, alkyl,cycloalkyl, —C(O)R⁹, —R¹⁰-cycloalkyl, —R¹⁰OR⁹, —R¹⁰NR⁹R¹¹ and —R¹⁰CO₂R⁹,or any subset thereof. More particularly, R⁷ and R⁸ are each the same ordifferent and are each independently selected from the group consistingof H, alkyl, cycloalkyl, and —R¹⁰-cycloalkyl, or any subset thereof. Inone embodiment, R⁷ and R⁸ are each the same or different and are eachindependently selected from the group consisting of H, alkyl andcycloalkyl.

[0101] The group —R¹⁰(OR¹⁰)_(w) in the definition of R⁹ and R¹¹ refersto a PEG-like chain. In one embodiment, R⁹ and R¹¹ are each the same ordifferent and are each independently selected from the group consistingof H, alkyl, cycloalkyl, and —R¹⁰-cycloalkyl, or any subset thereof.More particularly, R⁹ and R¹¹ are each the same or different and areeach independently selected from the group consisting of H and alkyl.

[0102] In one embodiment, R¹⁰ is alkyl or cycloalkyl. In one embodiment,R¹⁰ is alkyl. In another embodiment, the compounds of formula (I)include those compounds defined where R² does not contain an aryl,heterocyclic or heteroaryl moiety (or in one embodiment, R² does notcontain a heterocyclic or heteroaryl moiety but may contain an arylmoiety). A particular embodiment includes those compounds of formula (I)where R² does contain an aryl, heterocyclic or heteroaryl moiety. Basedon the guidance given above for R¹, one skilled in the art can readilydetermine the list of appropriate groups defining R² which contain orexclude aryl, heterocyclic or heteroaryl moeities.

[0103] In one embodiment, R² is selected from the group consisting ofAy, Het, —OR⁷, —OHet, —OR¹⁰Het, —S(O)_(n)R⁹, —NR⁷R⁸, —NHHet, —NHR¹⁰Hetand —R¹⁰NR⁷R⁸, or any subset thereof. In one particular embodiment, R²is selected from the group consisting of Het, —NR⁷R⁸, —NHHet and—NHR¹⁰Het, or any subset thereof. In one particular embodiment, thecompounds of formula (I) are defined wherein R² is selected from thegroup consisting of —NR⁷R⁸ and Het.

[0104] More specifically, in one embodiment, R² is selected from thegroup consisting of —NH₂, —NH-alkyl, —NH-cycloalkyl, —N(alkyl)(alkyl),Het, —O-alkyl, —N(alkyl)-O-alkyl, and —S-alkyl, or any subset thereof.

[0105] Specific examples of particular R² groups are selected from thegroup consisting of —NH₂, cyclopentylamine, cyclopropylamine,n-butylamine, pyrrolidine, —NCH₂CH₂OCH₃, —S-methyl, S-ethyl, andO-butyl, or any subset thereof.

[0106] In one class of compounds of formula (I), Y is CH. In anotherpreferred class of compounds of formula (I), Y is N.

[0107] In another embodiment, the compounds of formula (I) include thosecompounds defined where at least one of R³ and R⁴ contains an aryl,heterocyclic or heteroaryl moiety (or contains a heterocyclic orheteroaryl moiety but exclude aryl moeities). Another embodimentincludes those compounds of formula (I) where neither R³ nor R⁴ containan aryl, heterocyclic or heteroaryl moiety (or neither contains aheterocyclic or heteroaryl moiety but may contain an aryl moiety). Basedon the guidance given above for R¹, one skilled in the art can readilydetermine the list of appropriate groups defining R³ and R⁴ whichcontain or exclude aryl, heterocyclic and/or heteroaryl moeities.

[0108] In one embodiment, R³ is selected from the group consisting of H,halo, alkyl, Ay, —OR⁷, —CO₂R⁷, —NR⁷R⁸, —R¹⁰OR⁷ and —R¹⁰NR⁷R⁸, or anysubset thereof. More particularly, R³ is selected from the groupconsisting of H, halo, alkyl, —OR⁷, and —NR⁷R⁸, or any subset thereof.In one particular embodiment, R³ is H or alkyl. In one embodiment R³ isH. In one particular embodiment, when Y is CH, R³ is not —NR⁷Ay.

[0109] In one embodiment, R⁴ is selected from the group consisting of H,halo, alkyl, Ay, —OR⁷, —CO₂R⁷, —NR⁷R⁸, —R¹⁰OR⁷ and —R¹⁰NR⁷R⁸, or anysubset thereof. More particularly, R⁴ is selected from the groupconsisting of H, halo, alkyl —OR⁷, and —NR⁷R⁸, or any subset thereof. Inone embodiment, R⁴ is H or alkyl. In one embodiment R⁴ is H.

[0110] in formula (I) above is herein referred to as Ring A.

[0111] Ring A is a heterocyclic or heteroaryl group having from 5 to 10members (including 1, 2, 3 or 4 heteroatoms selected from N, O and S).

[0112] Ring A may be bonded to the pyrazolopyridine core through anyavailable atom including any available heteroatom. In one embodiment,Ring A contains at least one N atom and is bonded to thepyrazolopyridine core through N.

[0113] Examples of heterocyclic or heteroaryl groups having 5-10 memberswhich are suitable as Ring A are selected from the group consisting offuran, pyridine, pyrimidine, thiazole, pyrazine, pyrrole, imidazole,oxazole, benzimidazole, quinoline, isoquinoline, and quinoxoline, or anysubset thereof.

[0114] In one embodiment, Ring A is a heterocyclic or heteroaryl grouphaving 9 members. In one particular embodiment, Ring A is a aheterocyclic or heteroaryl group having 5 or 6 members.

[0115] In one embodiment, Ring A in formula (I) is selected from thegroup consisting of furan, thiazole, pyridine and pyrimidine.

[0116] In one particular embodiment, q is selected from the groupconsisting of 0, 1 and 2. In one embodiment, q is 0. In one embodiment,q is 1.

[0117] R⁵ may be in any suitable position on the heterocyclic orheteroaryl ring. R⁵ may be bound to a carbon atom or to a suitableheteroatom (i.e., N). One skilled in the art will readily be able toascertain suitable positions for attachment of the substituent(s) R⁵.

[0118] One class of compounds of formula (I) includes those compoundsdefined wherein at least one of R⁵ contains an aryl, heterocyclic orheteroaryl moiety (in one embodiment, a heterocyclic or heteroarylmoiety). Another class of compounds of formula (I) includes thosecompounds defined wherein no R⁵ contains an aryl, heterocyclic orheteroaryl moiety (in one embodiment, a heterocyclic or heteroarylmoiety). Based on the guidance given above for R¹, one skilled in theart can readily determine the list of appropriate groups defining R⁵which contain or exclude aryl, heterocyclic or heteroaryl moeities.

[0119] In one embodiment, each R⁵ is the same or different and isindependently selected from the group consisting of halo, alkyl,alkenyl, Ay, Het, —OR⁷, —OAy, —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)NR⁷Ay,—S(O)₂NR⁷R⁸, —NR⁷R⁸, —NR⁷Ay, —NHR¹⁰Ay, cyano, nitro and azido, or anysubset thereof. More particularly, each R⁵ is the same or different andis independently selected from the group consisting of halo, alkyl,alkenyl, Ay, Het, —OR⁷, —NR⁷R⁸, —NR⁷Ay, cyano, nitro, and azido, or anysubset thereof. In one particular embodiment, each R⁵ is the same ordifferent and is independently selected from the group consisting ofhalo, alkyl, —OR⁷, —NR⁷R⁸, cyano, nitro, and azido, or any subsetthereof. A few specific embodiments of the compounds of formula (I) aredefined where R⁵ is selected from the group consisting of halo (e.g.,fluoro or chloro), alkyl (e.g., methyl), O-alkyl (e.g., O-methyl,O-isobutyl, and

[0120] O-allyl, cyano, —NH—CH₃, —N(CH₃)₂, nitro and azido, or any subsetthereof.

[0121] It is to be understood that the present invention includes allcombinations and subsets of the specifically mentioned and particulargroups defined hereinabove.

[0122] Specific examples of compounds of formula (I) include but are notlimited to:

[0123]N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-pyridinyl)pyrazolo[1,5-a]pyridin-7-amine;

[0124]N-Cyclopentyl-3-[2-(methylamino)-4-pyrimidinyl]-2-(4-pyridinyl)pyrazolo[1,5-a]pyridin-7-amine;

[0125]N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(3-pyridinyl)pyrazolo[1,5-a]pyridin-7-amine;

[0126]N-Cyclopentyl-N-(4-{2-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-3-yl}-2-pyrimidinyl)amine;

[0127]N-(4-{7-Chloro-2-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-3-yl}-2-pyrimidinyl)-N-cyclopentylamine;

[0128]N-Cyclopentyl-2,3-bis[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine;

[0129]N-(2-Methoxyethyl)-2,3-bis{2-[(2-methoxyethyl)amino]pyrimidin-4-yl}pyrazolo[1,5-a]pyridin-7-amine;

[0130]N-Butyl-2,3-bis[2-(butylamino)pyrimidin-4-yl]pyrazolo[1,5-a]pyridin-7-amine;

[0131]N-Cyclopropyl-2,3-bis[2-(cyclopropylamino)pyrimidin-4-yl]pyrazolo[1,5-a]pyridin-7-amine;

[0132]7-Morpholin-4-yl-2,3-bis(2-morpholin-4-ylpyrimidin-4-yl)pyrazolo[1,5-a]pyridine;

[0133]N-Isobutyl-2,3-bis[2-(isobutylamino)pyrimidin-4-yl]pyrazolo[1,5-a]pyridin-7-amine;

[0134]N-Benzyl-2,3-bis[2-(benzylamino)pyrimidin-4-yl]pyrazolo[1,5-a]pyridin-7-amine;N-Isopropyl-2,3-bis[2-(isopropylamino)pyrimidin-4-yl]pyrazolo[1,5-a]pyridin-7-amine;

[0135]2-(2-Fluoro-4-pyridinyl)-3-[2-(methylsulfanyl)-4-pyrimidinyl]pyrazolo[1,5-a]pyridine;

[0136]4-[2-(2-Fluoro-4-pyridinyl)pyrazolo[1,5-a]pyridin-3-yl]-N-isopropyl-2-pyrimidinamine;

[0137]N-Isopropyl-4-{2-[2-(isopropylamino)-4-pyridinyl]pyrazolo[1,5-a]pyridin-3-yl}-2-pyrimidinamine;

[0138]3-[2-(Cyclopropylamino)-4-pyrimidinyl]-N-isopropyl-2-[2-(isopropylamino)-4-pyridinyl]pyrazolo[1,5-a]pyridin-7-amine;

[0139]N-Cyclopentyl-2-[2-(cyclopentylamino)-4-pyridinyl]-3-[2-(isopropylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine;

[0140]3-[2-(Cyclopentylamino)-4-pyrimidinyl]-N-isopropyl-2-[2-(isopropylamino)-4-pyridinyl]pyrazolo[1,5-a]pyridin-7-amine;

[0141]N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-[2-(isopropylamino)-4-pyridinyl]pyrazolo[1,5-a]pyridin-7-amine;

[0142]N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyridinyl]-2-(2-furyl)pyrazolo[1,5-a]pyridin-7-amine;

[0143]N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(3-methyl-2-furyl)pyrazolo[1,5-a]pyridin-7-amine;

[0144]N-Cyclopentyl-3-[2-(cyclopropylamino)-4-pyrimidinyl]-2-(3-methyl-2-furyl)pyrazolo[1,5-a]pyridin-7-amine;

[0145]N-Cyclopropyl-3-[2-(cyclopropylamino)-4-pyrimidinyl]-2-(3-methyl-2-furyl)pyrazolo[1,5-a]pyridin-7-amine;

[0146]N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(2-furyl)pyrazolo[1,5-a]pyridin-7-amine;

[0147]3-[2-(Cyclopentylamino)-4-pyrimidinyl]-N-cyclopropyl-2-(2-furyl)pyrazolo[1,5-a]pyridin-7-amine;

[0148]2-(5-Bromo-2-furyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine;and

[0149]N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyridinyl]-2-(2-methyl-1,3-thiazol-4-yl)pyrazolo[1,5-a]pyridin-7-amine;

[0150] and pharmaceutically acceptable salts, solvates andphysiologically functional derivatives thereof.

[0151] It will be appreciated by those skilled in the art that thecompounds of the present invention may also be utilized in the form of apharmaceutically acceptable salt, solvate or physiologically functionalderivative thereof. The pharmaceutically acceptable salts of thecompounds of formula (I) include conventional salts formed frompharmaceutically acceptable inorganic or organic acids or bases as wellas quaternary ammonium salts. More specific examples of suitable acidsalts include hydrochloric, hydrobromic, sulfuric, phosphoric, nitric,perchloric, fumaric, acetic, propionic, succinic, glycolic, formic,lactic, maleic, tartaric, citric, palmoic, malonic, hydroxymaleic,phenylacetic, glutamic, benzoic, salicylic, fumaric, toluenesulfonic,methanesulfonic (mesylate), naphthalene-2-sulfonic, benzenesulfonichydroxynaphthoic, hydroiodic, malic, steroic, tannic and the like. Inone embodiment, the compounds of formula (I) are in the form of themesylate salt Other acids such as oxalic, while not in themselvespharmaceutically acceptable, may be useful in the preparation of saltsuseful as intermediates in obtaining the compounds of the invention andtheir pharmaceutically acceptable salts. More specific examples ofsuitable basic salts include sodium, lithium, potassium, magnesium,aluminium, calcium, zinc, N,N′-dibenzylethylenediamine, chloroprocaine,choline, diethanolamine, ethylenediamine, N-methylglucamine and procainesalts.

[0152] The term “solvate” as used herein refers to a complex of variablestoichiometry formed by a solute (a compound of formula (I)) and asolvent. Solvents, by way of example, include water, methanol, ethanol,or acetic acid.

[0153] The term “physiologically functional derivative” as used hereinrefers to any pharmaceutically acceptable derivative of a compound ofthe present invention, for example, an ester or an amide of a compoundof formula (I), which upon administration to an animal, particularly amammal, such as a human, is capable of providing (directly orindirectly) a compound of the present invention or an active metabolitethereof. See for example, Burger's Medicinal Chemistry And DrugDiscovery, 5th Edition, Vol 1: Principles And Practice.

[0154] Processes for preparing pharmaceutically acceptable salts,solvates and physiologically functional derivatives of the compounds offormula (I) are conventional in the art. See, e.g., Burger's MedicinalChemistry And Drug Discovery 5th Edition, Vol 1: Principles AndPractice.

[0155] As will be apparent to those skilled in the art, in the processesdescribed below for the preparation of compounds of formula (I), certainintermediates, may be in the form of pharmaceutically acceptable salts,solvates or physiologically functional derivatives of the compound.Those terms as applied to any intermediate employed in the process ofpreparing compounds of formula (I) have the same meanings as noted abovewith respect to compounds of formula (I). Processes for preparingpharmaceutically acceptable salts, solvates and physiologicallyfunctional derivatives of such intermediates are known in the art andare analogous to the process for preparing pharmaceutically acceptablesalts, solvates and physiologically functional derivatives of thecompounds of formula (I).

[0156] Certain compounds of formula (I) and intermediates used in theprocesses of preparing compounds of formula (I) may exist instereoisomeric forms (e.g. they may contain one or more asymmetriccarbon atoms or may exhibit cis-trans isomerism). The individualstereoisomers (enantiomers and diastereomers) and mixtures of these areincluded within the scope of the present invention. The presentinvention also covers the individual isomers of the compoundsrepresented by formula (I) as mixtures with isomers thereof in which oneor more chiral centers are inverted. Likewise, it is understood thatcompounds of formula (I) may exist in tautomeric forms other than thatshown in the formula and these are also included within the scope of thepresent invention.

[0157] The present invention further provides compounds of formula (I)for use in medical therapy, e.g. in the treatment or prophylaxis,including suppression of recurrence of symptoms, of a viral disease inan animal, e.g. a mammal such as a human. The compounds of formula (I)are especially useful for the treatment or prophylaxis of viral diseasessuch as herpes viral infections. Herpes viral infections include, forexample, herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2),cytomegalovirus (CMV)) (including CMV in organ transplant patients beingtreated with immunosupressants), Epstein Barr virus (EBV), varicellazoster virus (VZV), human herpes virus 6 (HHV-6), human herpes virus 7(HHV-7), and human herpes virus 8 (HHV-8). Thus, the compounds of theinvention are also useful in the treatment or prophylaxis of thesymptoms or effects of herpes virus infections.

[0158] The compounds of the invention are useful in the treatment orprophylaxis of conditions or diseases associated with herpes virusinfections, particularly conditions or diseases associated with latentherpes virus infections in an animal, e.g., a mammal such as a human. Byconditions or diseases associated with herpes viral infections is meanta condition or disease, excluding the viral infection per se, whichresults from the presence of the viral infection, such as chronicfatigue syndrome which is associated with EBV infection; and multiplesclerosis which has been associated with herpes viral infections such asEBV and HHV-6. Further examples of such conditions or diseases aredescribed in the background section above.

[0159] In addition to those conditions and diseases, the compounds ofthe present invention may also be used for the treatment or prophylaxisof cardiovascular diseases and conditions associated with herpes virusinfections, in particular atherosclerosis, coronary artery disease andrestenosis and specifically restenosis following angioplasty (RFA).Restenosis is the narrowing of the blood vessels which can occur afterinjury to the vessel wall, for example injury caused by balloonangioplasty or other surgical and/or diagnostic techniques, and ischaracterized by excessive proliferation of smooth muscle cells in thewalls of the blood vessel treated. It is thought that in many patientssuffering from restenosis following angioplasty, viral infection,particularly by CMV and/or HHV-6 plays a pivotal role in theproliferation of the smooth muscle cells in the coronary vessel.Restenosis can occur following a number of surgical and/or diagnostictechniques, for example, transplant surgery, vein grafting, coronaryby-pass grafting and, most commonly following angioplasty.

[0160] There is evidence from work done both in vitro and in vivo,indicating that restenosis is a multifactorial process. Severalcytokines and growth factors, acting in concert, stimulate the migrationand proliferation of vascular smooth muscle cells (SMC) and productionof extracellular matrix material, which accumulate to occlude the bloodvessel. In addition growth suppressors act to inhibit the proliferationof SMC's and production of extracellular matrix material.

[0161] In addition, compounds of formula (I) may be useful in thetreatment or prophylaxis of hepatitis B and hepatitis C viruses, humanpapilloma virus (HPV) and HIV.

[0162] The present invention provides a method for the treatment orprophylaxis of a viral infection in an animal such as a mammal (e.g., ahuman), particularly a herpes viral infection, which method comprisesadministering to the animal a therapeutically effective amount of thecompound of formula (I).

[0163] As used herein, the term “prophylaxis” refers to the preventionof infection, the prevention of occurrence of symptoms in an infectedsubject, the prevention of recurrence of symptoms in an infectedsubject, or a decrease in severity or frequency of symptoms of viralinfection, condition or disease in the subject.

[0164] As used herein, the term “treatment” refers to the partial ortotal elimination of symptoms or decrease in severity of symptoms ofviral infection, condition or disease in the subject, or the eliminationor decrease of viral presence in the subject

[0165] As used herein, the term “therapeutically effective amount” meansan amount of a compound of formula (I) which is sufficient, in thesubject to which it is administered, to treat or prevent the stateddisease, condition or infection. For example, a therapeuticallyeffective amount of a compound of formula (I) for the treatment of aherpes virus infection is an amount sufficient to treat the herpes virusinfection in the subject.

[0166] The present invention also provides a method for the treatment orprophylaxis of conditions or diseases associated with herpes viralinfections in an animal such as a mammal (e.g., a human), whichcomprises administering to the animal a therapeutically effective amountof the compound of formula (I). In one embodiment, the present inventionprovides a method for the treatment or prophylaxis of chronic fatiguesyndrome or multiple sclerosis in an animal such as a mammal (e.g., ahuman), which comprises administering to the animal a therapeuticallyeffective amount of a compound of formula (I). The foregoing method isparticularly useful for the treatment or prophylaxis of chronic fatiguesyndrome or multiple sclerosis associated with latent infection with aherpes virus.

[0167] In another embodiment, the present invention provides a methodfor the treatment or prophylaxis of a cardiovascular condition such asatherosclerosis, coronary artery disease or restenosis (particularlyrestenosis following surgery such as angioplasty), which comprisesadministering to the animal a therapeutically effective antiviral amountof the compound of formula (I).

[0168] The present invention further provides a method for the treatmentor prophylaxis of hepatitis B or hepatitis C viruses in an animal suchas a mammal (e.g., a human), which comprises administering to the animala therapeutically effective amount of the compound of formula (I).

[0169] The present invention further provides a method for the treatmentor prophylaxis of human papilloma virus in an animal such as a mammal(e.g., a human), which comprises administering to the animal atherapeutically effective amount of the compound of formula (I).

[0170] The present invention further provides a method for the treatmentor prophylaxis of HIV in an animal such as a mammal (e.g., a human),which comprises administering to the animal a therapeutically effectiveamount of the compound of formula (I).

[0171] The present invention also provides the use of the compound offormula (I) in the preparation of a medicament for the treatment orprophylaxis of a viral infection in an animal such as a mammal (e.g., ahuman), particularly a herpes viral infection; the use of the compoundof formula (I) in the preparation of a medicament for the treatment of acondition or disease associated with a herpes viral infection; and theuse of the compound of formula (I) in the preparation of a medicamentfor the treatment or prophylaxis of hepatitis B or hepatitis C viruses,human papilloma virus or HIV. In particular, the present invention alsoprovides the use of a compound of formula (I) in the preparation of amedicament for the treatment or prophylaxis of chronic fatigue syndromeor multiple sclerosis. In one embodiment, the present invention providesthe use of a compound of formula (I) in the preparation of a medicamentfor the treatment or prophylaxis of cardiovascular disease, such asrestenosis or atherosclerosis.

[0172] The compounds of formula (I) are conveniently administered in theform of pharmaceutical compositions. Such compositions may convenientlybe presented for use in conventional manner in admixture with one ormore physiologically acceptable carriers or diluents.

[0173] While it is possible that compounds of the present invention maybe therapeutically administered as the raw chemical, it is preferable topresent the active ingredient as a pharmaceutical composition. Thepharmaceutical composition may further comprise one or morepharmaceutically acceptable carriers or diluents together with thecompound of formula (I). The carrier(s) or diluents must be “acceptable”in the sense of being compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

[0174] Accordingly, the present invention further provides for apharmaceutical composition or formulation comprising a compound offormula (I). In one embodiment, the pharmaceutical formulation furthercomprises one or more pharmaceutically acceptable carriers or dilentsand, optionally, other therapeutic and/or prophylactic ingredients.

[0175] The formulations include those suitable for oral, parenteral(including subcutaneous e.g. by injection or by depot tablet,intradermal, intrathecal, intramuscular e.g. by depot and intravenous),rectal and topical (including dermal, buccal and sublingual)administration although the most suitable route may depend upon forexample the condition, age, and disorder of the recipient as well as theviral infection or disease being treated. The formulations mayconveniently be presented in unit dosage form and may be prepared by anyof the methods well known in the art of pharmacy. All methods includethe step of bringing into association the compound(s) (“activeingredient”) with the carrier which constitutes one or more accessoryingredients. In general the formulations are prepared by uniformly andintimately bringing into association the active ingredient with liquidcarriers or finely divided solid carriers or both and then, ifnecessary, shaping the product into the desired formulation.Formulations suitable for oral administration may be presented asdiscrete units such as capsules (including soft-gel capsules), cachetsor tablets (e.g. chewable tablets in particular for paediatricadministration) each containing a predetermined amount of the activeingredient; as a powder or granules; as a solution or a suspension in anaqueous liquid or a non-aqueous liquid; or as an oil-in-water liquidemulsion or a water-in-oil liquid emulsion. The active ingredient mayalso be presented as a bolus, electuary or paste.

[0176] A tablet may be made by compression or moulding, optionally withone or more accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active ingredient in afree-flowing form such as a powder or granules, optionally mixed withother conventional excipients such as binding agents, (for example,syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch orpolyvinylpyrrolidone), fillers (for example, lactose, sugar,microcrystalline cellulose, maize-starch, calcium phosphate orsorbitol), lubricants (for example, magnesium stearate, stearic acid,talc, polyethylene glycol or silica), disintegrants (for example, potatostarch or sodium starch glycollate) or wetting agents, such as sodiumlauryl sulfate. Moulded tablets may be made by moulding in a suitablemachine a mixture of the powdered compound moistened with an inertliquid diluent. The tablets may optionally be coated or scored and maybe formulated so as to provide slow or controlled release of the activeingredient therein. The tablets may be coated according to methodswell-known in the art.

[0177] Alternatively, the compounds of the present invention may beincorporated into oral liquid preparations such as aqueous or oilysuspensions, solutions, emulsions, syrups or elixirs, for example.Moreover, formulations containing these compounds may be presented as adry product for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may contain conventional additives such assuspending agents such as sorbitol syrup, methyl cellulose,glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fats;emulsifying agents such as lecithin, sorbitan mono-oleate or acacia;non-aqueous vehicles (which may include edible oils) such as almond oil,fractionated coconut oil, oily esters, propylene glycol or ethylalcohol; and preservatives such as methyl or propyl p-hydroxybenzoatesor sorbic acid. Such preparations may also be formulated assuppositories, e.g., containing conventional suppository bases such ascocoa butter or other glycerides. Liquid preparations may also beformulated as soft-gel capsules for oral administration, e.g.,containing conventional soft-gel excipients such as polyethylene glycol.

[0178] Formulations for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents.

[0179] The formulations may be presented in unit-dose or multi-dosecontainers, for example sealed ampoules and vials, and may be stored ina freeze-dried (lyophilised) condition requiring only the addition of asterile liquid carrier, for example, water-for-injection, immediatelyprior to use. Extemporaneous injection solutions and suspensions may beprepared from sterile powders, granules and tablets of the kindpreviously described. Formulations for rectal administration may bepresented as a suppository with the usual carriers such as cocoa butter,hard fat or polyethylene glycol.

[0180] Formulations for topical (e.g., dermal) or intranasaladministration include ointments, creams, lotions, pastes, gels, sprays,aerosols and oils. Suitable carriers for such formulations includingpetroleum jelly, lanolin, polyethylene glycols, alcohols, andcombinations thereof.

[0181] Formulations for topical administration in the mouth, for examplebuccally or sublingually, include lozenges comprising the activeingredient in a flavoured base such as sucrose and acacia or tragacanth,and pastilles comprising the active ingredient in a base such as gelatinand glycerin or sucrose and acacia.

[0182] The compounds may also be formulated as depot preparations. Suchlong acting formulations may be administered by implantation (forexample subcutaneously or intramuscularly) or by intramuscularinjection. Thus, for example, the compounds may be formulated withsuitable polymeric or hydrophobic materials (for example as an emulsionin an acceptable oil) or ion exchange resins, or as sparingly solublederivatives, for example, as a sparingly soluble salt.

[0183] In addition to the ingredients particularly mentioned above, theformulations may include other agents conventional in the art havingregard to the type of formulation in question, for example thosesuitable for oral administration may include flavouring agents.

[0184] It will be appreciated that the amount of a compound of theinvention required for use in treatment will vary with the nature of thecondition being treated and the age and the condition of the patient andwill be ultimately at the discretion of the attendant physician orveterinarian. In general, however, doses employed for adult humantreatment will typically be in the range of 0.02-5000 mg per day,preferably 100-1500 mg per day. The desired dose may conveniently bepresented in a single dose or as divided doses administered atappropriate intervals, for example as two, three, four or more sub-dosesper day. The formulations according to the invention may contain between0.1-99% of the active ingredient, conveniently from 30-95% for tabletsand capsules and 3-50% for liquid preparations.

[0185] The compound of formula (I) for use in the instant invention maybe used in combination with other therapeutic agents for example,non-nucleoside reverse transcriptase inhibitors, nucleoside reversetranscriptase inhibitors, protease inhibitors and/or other antiviralagents. The invention thus provides in a further aspect the use of acombination comprising a compound of formula (I) with a furthertherapeutic agent in the treatment of viral infections. Particularantiviral agents which may be combined with the compounds of the presentinvention include aciclovir, valaciclovir, famcyclovir, ganciclovir,docosanol, miribavir, amprenavir, lamivudine, zidovudine, and abacavir.Preferred antiviral agents for combining with the compounds of thepresent invention include aciclovir, famcyclovir and valaciclovir. Thusthe present invention provides in a further aspect, a combinationcomprising a compound of formula (I) and an antiviral agent selectedfrom the group consisting of aciclovir or valaciclovir; the use of suchcombination in the treatment of viral infections and the preparation ofa medicament for the treatment of viral infections, and a method oftreating viral infections comprising administering a compound of formula(I) and an antiviral agent selected from the group consisting ofaciclovir and valaciclovir.

[0186] When the compounds of formula (I) are used in combination withother therapeutic agents, the compounds may be administered eithersequentially or simultaneously by any convenient route.

[0187] The combinations referred to above may conveniently be presentedfor use in the form of a pharmaceutical formulation and thuspharmaceutical formulations comprising a combination as defined aboveoptionally together with a pharmaceutically acceptable carrier ordiluent comprise a further aspect of the invention. The individualcomponents of such combinations may be administered either sequentiallyor simultaneously in separate or combined pharmaceutical formulations.

[0188] When combined in the same formulation it will be appreciated thatthe two compounds must be stable and compatible with each other and theother components of the formulation and may be formulated foradministration. When formulated separately they may be provided in anyconvenient formulation, in such a manner as are known for such compoundsin the art.

[0189] When a compound of formula (I) is used in combination with asecond therapeutic agent active against the viral infection, the dose ofeach compound may differ from that when the compound is used alone.Appropriate doses will be readily appreciated by those skilled in theart.

[0190] Compounds of formula (I) wherein Y is N, and R³ and R⁴ are H, maybe conveniently prepared by the process outlined in Scheme 1 below.

[0191] wherein:

[0192] p is 0, 1, 2, 3 or 4;

[0193] p′ is 0, 1, 2 or 3;

[0194] each R¹ is the same or different and is independently selectedfrom the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OR¹⁰Ay, —OHet, —OR¹⁰Het, —C(O)R⁹,—C(O)Ay, —C(O)Het, —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(O)NHR¹⁰Ay,—C(O)NHR¹⁰Het, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —S(O)_(n)R⁹,—S(O)_(n)Ay, —S(O)_(n)Het, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —NR⁷R⁸, —NR⁷Ay,—NHHet, —NHR¹⁰Ay, —NHR¹⁰Het, —R¹⁰cycloalkyl, —R¹⁰Ay, —R¹⁰Het,—R¹⁰O—C(O)R⁹, —R¹⁰O—C(O)Ay, —R¹⁰O—C(O)Het, —R¹⁰O—S(O)_(n)R⁹, —R¹⁰OR⁹,—R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(O)NR⁷Ay, —R¹⁰C(O)NHR¹⁰Het,—R¹⁰C(S)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹, —R¹⁰SO₂NR⁹R¹¹,—R¹⁰SO₂NHCOR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰NHC(NH)NR⁹R¹¹, cyano, nitro andazido;

[0195] or two adjacent R¹ groups together with the carbon atoms to whichthey are bonded form a cycloalkyl or a 5- or 6-membered heterocyclicgroup containing 1 or 2 heteroatoms;

[0196] each R⁷ and R⁸ are the same or different and are independentlyselected from the group consisting of H, alkyl, alkenyl, cycloalkyl,cycloalkenyl, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁹R¹¹, —C(S)NR⁹R¹¹, —C(NH)NR⁹R¹¹,—SO₂R¹⁰, —SO₂NR⁹R¹¹, —R¹⁰cycloalkyl. —R¹⁰OR⁹, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹,—R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R¹⁰,—R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂NHCOR⁹, —R¹⁰NR⁹R¹¹, —R¹⁰NHCOR⁹, —R¹⁰NHSO₂R⁹ and—R¹⁰NHC(NH)NR⁹R¹¹;

[0197] each R⁹ and R¹¹ are the same or different and are independentlyselected from the group consisting of H, alkyl, cycloalkyl,—R¹⁰cycloalkyl, —R¹⁰OH, —R¹⁰(OR¹⁰)_(w) wherein w is 1-10, and—R¹⁰NR¹⁰R¹⁰;

[0198] each R¹⁰ is the same or different and is independently selectedfrom the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl andcycloalkenyl;

[0199] Ay is aryl;

[0200] Het is a 5- or 6-membered heterocyclic or heteroaryl group;

[0201] Y is N;

[0202] R² is selected from the group consisting of halo, alkyl, alkenyl,cycloalkyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Het,—S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸, —NHHet,—NHR¹⁰Ay, —NHR¹⁰Het, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay;

[0203] n is 0, 1 or 2;

[0204] R³ and R⁴ are H;

[0205] Ring A is a heterocyclic or heteroaryl group having from 5 to 10members;

[0206] q is 0, 1, 2, 3, 4 or 5; and

[0207] each R⁵ is the same or different and is independently selectedfrom the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OR¹⁰Ay, —OHet, —OR¹⁰Het, —C(O)R⁹,—C(O)Ay, —C(O)Het, —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(O)NHR¹⁰Het,—C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —S(O)_(n)R⁹, —S(O)₂NR⁷R⁸,—S(O)₂NR⁷Ay, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay, —NHR¹⁰Het,—R¹⁰cycloalkyl, —R¹⁰Het, —R¹⁰OR⁹, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹,—R¹⁰C(O)NR⁷Ay, —R¹⁰C(O)NHR¹⁰Het, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹,—R¹⁰SO₂R⁹, —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂NHCOR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay,—R¹⁰NHC(NH)NR⁹R¹¹, cyano, nitro and azido;

[0208] Rg is Ay or Het as defined above;

[0209] M³ is B(OH)₂, B(ORa)₂, B(Ra)₂, Sn(Ra)₃, Zn-halide, Zn—Ra orMg-halide; and

[0210] Ra is alkyl or cycloalkyl; and all other variables are definedabove.

[0211] Generally, the process for preparing the compounds of formula (I)wherein Y is N and R³ and R⁴ are H, (all formulas and all othervariables having been defined above in connection with Scheme 1)comprises the steps of:

[0212] (a) reacting a picoline with an ester of formula (II) to preparea compound of formula (III);

[0213] (b) reacting the compound of formula (III) with a hydroxylaminesource to prepare a compound of formula (IV);

[0214] (c) reacting the compound of formula (IV) with an acylating orsulfonylating agent to prepare a compound of formula (V);

[0215] (d) rearranging the compound of formula (V) to prepare a compoundof formula (VI);

[0216] (e) acylating the compound of formula (VI) to prepare a compoundof formula (VII);

[0217] (f) when at least one R¹ is halogen (i.e., a compound of formula(VII-A)), either:

[0218] (1) replacing the halogen of the compound of formula (VII-A) withan amine to prepare a compound of formula (VII); or

[0219] (2) coupling the compound of formula (VII-A) with a metalcompound of formula Rg-M³ to prepare a compound of formula (VII);

[0220] (g) reacting the compound of formula (VII) with adimethylformamide dialkyl acetal of formula (CH₃)₂NCH(ORa)₂ to prepare acompound of formula (IX); and

[0221] (h) reacting the compound of formula (IX) with a compound offormula (X) to prepare a compound of formula (I).

[0222] More specifically, compounds of formula (I) wherein Y is N and R³and R⁴ are H can be prepared by reacting a compound of formula (IX) witha compound of formula (X).

[0223] wherein all variables are as defined above in connection withScheme 1.

[0224] This method can be readily carried out by mixing a compound offormula (IX) with a compound of formula (X) in a suitable solvent,optionally in the presence of a base (particularly when the amidine isin a salt form), and heating the reaction to 50-150° C. Typical solventsinclude lower alcohols such as methanol, ethanol, isopropanol and thelike and N,N-dimethylformamide. The base is typically a sodium alkoxide,potassium carbonate, or an amine base such as triethylamine. In oneembodiment, the solvent is N,N-dimethylformamide and the base ispotassium carbonate, or an amine base such as triethylamine.

[0225] Compounds of formula (IX) may be conveniently prepared byreacting a compound of formula (VII) with a dimethylformamide dialkylacetal, wherein R_(a) is alkyl or cycloalkyl.

[0226] wherein all variables are as defined above in connection withScheme 1.

[0227] Typical dimethylformamide dialkylacetal compounds for use in thismethod include but are not limited to dimethylformamide dimethylacetaland dimethylformamide di-tert-butylacetal. The reaction is carried outby mixing a compound of formula (VII) with the dimethylformamide dialkylacetal, optionally with heating.

[0228] For a compound of formula (VII-A) where at least one R¹ ishalogen a compound of the formula (VII) may be prepared by two generalmethods. According to one method, a compound of formula (VII) isprepared from a compound of formula (VII-A) by replacement of thehalogen with an amine nucleophile.

[0229] wherein all variables are as defined above in connection withScheme 1.

[0230] Typically the replacement is carried out by mixing the compoundof formula (VII-A) with an amine nucleophile selected from the groupconsisting of —NHR¹⁰Ay, —NR⁷Ay, Het, —NHHet, —NHR¹⁰Het and —NR⁷R⁸; andoptionally heating the reaction. The reaction can also be carried outvia an adaptation of procedures found in the literature (Wolfe, J. P.;Buchwald, S. L. J. Org. Chem. 2000, 65, 1144) wherein a compound offormula (VII-A) is treated with an amine, a palladium (O) or nickel (O)source and a base in a suitable solvent. Suitable sources of palladium(O) include but are not limited to palladium(II) acetate andtris(dibenzylideneacetone) dipalladium (O). Typical bases for use in thereaction include, for example sodium tert-butoxide and cesium carbonate.Toluene is an example of a suitable solvent.

[0231] According to the second method, a compound of formula (VII-A) isconverted to a compound of formula (VII) by coupling with a metalcompound of formula Rg-M³ wherein Rg is Ay or Het and M³ is B(OH)₂,B(ORa)₂, B(Ra)₂, Sn(Ra)₃, Zn-halide; Zn—Ra or Mg-halide, wherein Ra isalkyl or cycloalkyl and halide is halo. This general method can beconveniently performed in an inert solvent, in the presence of apalladium (O) catalyst, optionally with heating. In an embodiment, thereaction is performed by reacting equimolar amounts of a compound offormula (VII-A) with the metal compound of formula Rg-M³ or optionallyadding an excess of the metal compound. The palladium catalyst istypically present in 1-10 mol % compared to the compound of formula(VII-A). Palladium catalysts that may be used may include, but are notlimited to, tetrakistriphenylphosphine palladium (O)dichlorobis(triphenylphosphine)-palladium(II), andbis(diphenylphosphinoferrocene)-palladium (II) dichloride. Inertsolvents for use in the reaction include but are not limited to,N,N-dimethylformamide, toluene, tetrahydrofuran, dioxane, and1-methyl-2-pyrrolidinone.

[0232] When the metal compound of formula Rg-M³ is an arylboronic acidor ester or an arylborinate, the reaction is more conveniently carriedout by adding a base in a proportion equivalent to, or greater than,that of the metal compound.

[0233] Metal compounds of formula Rg-M³ can be purchased from commercialsources or prepared either as discreet isolated compounds or generatedin situ using methods known to one skilled in the art (Suzuki, A. J.Organomet. Chem. 1999, 576, 147; Stille, J. Angew. Chem. Int. Ed. Engl.1986, 25, 508; Snieckus, V. J. Org. Chem. 1995, 60, 292.)

[0234] Compounds of the formula (VII) (including compounds of formula(VII-A) may be conveniently prepared from compounds of formula (VI)using an acylation procedure.

[0235] wherein all variables are as defined above in connection withScheme 1.

[0236] Typically the acylation is carried out by treating the compoundof formula (VI) with an acylating agent, optionally in the presence ofan acid or Lewis acid catalyst in an inert solvent with optionalheating. Typical acylating agents will be readily determined by thoseskilled in the art. One particular acylating agent is acetic anhydride.Lewis acid catalysts are also known to those skilled in the art. Oneparticular Lewis acid catalyst for use in this reaction is borontrifluoride diethyl etherate. A suitable solvent is toluene.

[0237] A compound of formula (VI) is conveniently prepared byrearranging an azirine compound of formula (V).

[0238] wherein all variables are as defined above in connection withScheme 1.

[0239] The rearrangement of the azirine of formula (V) can beaccomplished by heating a solution of the azirine of formula (V) in asuitable solvent at a temperature of about 160-200° C. Suitable inertsolvents include, but are not limited to, 1-methyl-2-pyrrolidinone, and1,2,4-trichlorobenzene. A particular method for rearrangement of theazirine of formula (V) to a compound of formula (VI) involves reactingthe compound of formula (V) with ferrous chloride (FeCl₂) or ferricchloride (FeCl₃). This reaction is typically done in an inert solventwith heating. A particular solvent for this reaction is1,2-dimethoxyethane and the like.

[0240] Typically the azirines of formula (V) are prepared from acorresponding oxime compound of formula (IV) by treatment with acylatingor sulfonylating agents in the presence of a base.

[0241] wherein all variables are as defined above in connection withScheme 1.

[0242] Typical acylating or sulfonylating agents include but are notlimited to, acetic anhydride, trifluoroacetic anhydride, methanesulfonylchloride, toluenesulfonyl chloride and the like. Typical bases include,but are not limited to, triethylamine, diisopropylethylamine, pyridine,and the like. The reaction may be carried out in an inert solvent suchas for example, chloroform, dichloromethane, toluene or the like.

[0243] The oxime compounds of formula (IV) are readily prepared bytreating a ketone compound of formula (III) with a hydroxylamine source,in a suitable solvent, and optionally with a base.

[0244] wherein all variables are as defined above in connection withScheme 1.

[0245] Typically the hydroxylamine is hydroxylamine hydrochloride andthe base is an aqueous solution of sodium hydroxide. Suitable solventsinclude lower alcohols such as methanol, ethanol, or isopropanol.

[0246] The ketone compounds of formula (III) can be prepared bytreatment of a picoline with an ester of formula (II) in the presence ofa base.

[0247] wherein all variables are as defined above in connection withScheme 1.

[0248] An example of a suitable base is lithium bis(trimethylsilyl)amidein an inert solvent such as tetrahydrofuran. Ketones such as those offormula (III) can be readily prepared using procedures known to oneskilled in the art and/or described in the literature (Cassity, R. P.;Taylor, L. T.; Wolfe, J. F. J. Org. Chem. 1978, 2286). Compounds offormula (II) are commercially available or can be prepared byconventional means.

[0249] In addition to the foregoing process for preparing certaincompounds of formula (I), the present invention also provides certainintermediate compounds for use in the preparation of such compounds offormula (I) according to the foregoing process. Such intermediates aredescribed in Scheme 1 above.

[0250] In a further embodiment of the present invention, compounds offormula (I) wherein Y is N; R³ is selected from the group consisting ofof H, alkyl, cycloalkyl, alkenyl, Ay, Het, —OR⁷, —OAy, —C(O)R⁷, C(O)Ay,—CO₂R⁷, —CO₂Ay, —SO₂NHR⁹, —NR⁷R⁸(where R⁷ and R⁸ are not H), —NR⁷Ay(where R⁷ is not H), —R¹⁰cycloalkyl, —R¹⁰OR⁷, —R¹⁰OAy, —R¹⁰NR⁷R⁸ and—R¹⁰NR⁷Ay; and R⁴ is H; and may be conveniently prepared by a processoutlined in Scheme 2 below.

[0251] wherein:

[0252] p is 0, 1, 2, 3 or 4;

[0253] each R¹ is the same or different and is independently selectedfrom the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OR¹⁰Ay, —OHet, —OR¹⁰Het, —C(O)R⁹,—C(O)Ay, —C(O)Het, —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(O)NHR¹⁰Ay,—C(O)NHR¹⁰Het, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —S(O)_(n)R⁹,—S(O)_(n)Ay, —S(O)_(n)Het, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —NR⁷R⁸, —NR⁷Ay,—NHHet, —NHR¹⁰Ay, —NHR¹⁰Het, —R¹⁰cycloalkyl, —R¹⁰Ay, —R¹⁰Het,—R¹⁰O—C(O)R⁹, —R¹⁰O—C(O)Ay, —R¹⁰O—C(O)Het, —R¹⁰O—S(O)_(n)R⁹, —R¹⁰OR⁹,—R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(O)NR⁷Ay, —R¹⁰C(O)NHR¹⁰Het,—R¹⁰C(S)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹, —R¹⁰SO₂NR⁹R¹¹,—R¹⁰SO₂NHCOR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰NHC(NH)NR⁹R¹¹, cyano, nitro andazido;

[0254] or two adjacent R¹ groups together with the carbon atoms to whichthey are bonded form a cycloalkyl or a 5- or 6-membered heterocyclicgroup containing 1 or 2 heteroatoms;

[0255] each R⁷ and R⁸ are the same or different and are independentlyselected from the group consisting of H, alkyl, alkenyl, cycloalkyl,cycloalkenyl, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁹R¹¹, —C(S)NR⁹R¹¹, —C(NH)NR⁹R¹¹,—SO₂R¹⁰, —SO₂NR⁹R¹¹, —R¹⁰cycloalkyl, —R¹⁰OR⁹, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹,—R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R¹⁰,—R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂NHCOR⁹, —R¹⁰NR⁹R¹¹, —R¹⁰NHCOR⁹, —R¹⁰NHSO₂R⁹ and—R¹⁰NHC(NH)NR⁹R¹¹;

[0256] each R⁹ and R¹¹ are the same or different and are independentlyselected from the group consisting of H, alkyl, cycloalkyl,—R¹⁰cycloalkyl, —R¹⁰OH, —R¹⁰(OR¹⁰)_(w) wherein w is 1-10, and—R¹⁰NR¹⁰R¹⁰;

[0257] each R¹⁰ is the same or different and is independently selectedfrom the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl andcycloalkenyl;

[0258] Ay is aryl;

[0259] Het is a 5- or 6-membered heterocyclic or heteroaryl group;

[0260] Y is N;

[0261] R² is selected from the group consisting of halo, alkyl, alkenyl,cycloalkyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Het,—S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸, —NHHet,—NHR¹⁰Ay, —NHR¹⁰Het, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay;

[0262] n is 0, 1 or 2;

[0263] R³ is selected from the group consisting of H, alkyl, cycloalkyl,alkenyl, Ay, Het, —OR⁷, —OAy, —C(O)R⁷, C(O)Ay, —CO₂R⁷, —CO₂Ay, —SO₂NHR⁹,—NR⁷R⁸ (where R⁷ and R⁸ are not H), —NR⁷Ay (where R⁷ is not H),—R¹⁰cycloalkyl, —R¹⁰OR⁷, —R¹⁰OAy, R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay;

[0264] R⁴ is H;

[0265] Ring A is a heterocyclic or heteroaryl group having from 5 to 10members;

[0266] q is 0, 1, 2, 3, 4 or 5;

[0267] each R⁵ is the same or different and is independently selectedfrom the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OR¹⁰Ay, —OHet, —OR¹⁰Het, —C(O)R⁹,—C(O)Ay, —C(O)Het, —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(O)NHR¹⁰Het,—C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —S(O)_(n)R⁹, —S(O)₂NR⁷R⁸,—S(O)₂NR⁷Ay, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay, —NHR¹⁰Het,—R¹⁰cycloalkyl, —R¹⁰Het, —R¹⁰OR⁹, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹,—R¹⁰C(O)NR⁷Ay, —R¹⁰C(O)NHR¹⁰Het, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰C(N H)NR⁹R¹¹,—R¹⁰SO₂R⁹, —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂NHCOR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay,—R¹⁰NHC(NH)NR⁹R¹¹, cyano, nitro and azido; and

[0268] M¹ is Li, Mg-halide or cerium-halide.

[0269] Generally, the process for preparing compounds of formula (I)wherein Y is N; R³ is selected from the group consisting of of H, alkyl,cycloalkyl, alkenyl, Ay, Het, —OR⁷, —OAy, —C(O)R⁷, C(O)Ay, —CO₂R⁷,—CO₂Ay, —SO₂NHR⁹, —NR⁷R⁸ (where R⁷ and R⁸ are not H), —NR⁷Ay (where R⁷isnot H), —R¹⁰cycloalkyl, —R¹⁰OR⁷, —R¹⁰OAy, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; andR⁴ is H; comprises the following steps:

[0270] (a) formylating a compound of formula (VI) to prepare a compoundof formula (XIII);

[0271] (b) reacting the compound of formula (XIII) with a compound offormula (XIV) to prepare a compound of formula (XV);

[0272] (c) oxidizing the compound of formula (XV) to prepare a compoundof formula (XVI); and

[0273] (d) reacting a compound of formula (XVI) with a compound offormula (X) to prepare a compound of formula (I).

[0274] More specifically, a compound of formula (I) may be prepared byreacting a compound of formula (XVI) with a compound of formula (X).

[0275] wherein all variables are as defined above in connection withScheme 2.

[0276] This method can be readily carried out by mixing a compound offormula (XVI) with a compound of formula (X) in a suitable solvent,optionally in the presence of a base. The reaction may be heated to50-150° C. or performed at ambient temperature. Typical solvents includebut are not limited to lower alcohols such as methanol, ethanol,isopropanol and the like. Typical bases include for example, sodiumalkoxide, potassium carbonate, or an amine base such as triethylamine.In another embodiment, the solvent is N,N-dimethylformamide and the baseis potassium carbonate, or an amine base such as triethylamine.

[0277] A compound of formula (XVI) may be conveniently prepared byoxidation of a compound of formula (XV).

[0278] wherein all variables are as defined above in connection withScheme 2.

[0279] Preferred oxidizing agents include but are not limited to,manganese dioxide, and the like, in an inert solvent. Suitable inertsolvents include but are not limited to, dichloromethane, chloroform,N,N-dimethylformamide, ether, and the like.

[0280] A compound of formula (XV) may be conveniently prepared byreacting a compound of formula (XIII) with a compound of formula (XIV).

[0281] wherein all variables are as defined above in connection withScheme 2.

[0282] Particular metals (M¹) in the compounds of formula (XIV) includebut are not limited to, lithium, magnesium(II) halides, cerium(II)halides, and the like. Compounds of formula (XIV) may be purchased fromcommercial sources or prepared by methods known to one skilled in theart.

[0283] A compound of formula (XIII) may be conveniently prepared from acompound of formula (VI) by a formylation procedure.

[0284] wherein all variables are as defined above in connection withScheme 2.

[0285] Typically the formulation is carried out via the Vilsmeier-Haackreaction. The Vilsmeier-Haack reagents can be purchased from commercialsources or prepared in situ. Typical conditions include, but are notlimited to treating compounds of formula (VI) with a premixed solutionof phosphorous oxychloride in N,N-dimethylformamide optionally withheating the reaction to 50-150° C.

[0286] The compounds of formula (VI) are prepared by the processdescribed in Scheme 1 above.

[0287] In addition to the foregoing process for preparing certaincompounds of formula (I), the present invention also provides certainintermediate compounds for use in the preparation of such compounds offormula (I) according to the foregoing process. Such intermediates aredescribed in Scheme 2 above.

[0288] A compound of formula (I) wherein Y is N may be convenientlyprepared by a process outlined in Scheme 3 below.

[0289] wherein:

[0290] p is 0, 1, 2, 3 or 4;

[0291] each R¹ is the same or different and is independently selectedfrom the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OR¹⁰Ay, —OHet, —OR¹⁰Het, —C(O)R⁹,—C(O)Ay, —C(O)Het, —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(O)NHR¹⁰Ay,—C(O)NHR¹⁰Het, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —S(O)_(n)R⁹,—S(O)Ay, —S(O)_(n)Het, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —NR⁷R⁸, —NR⁷Ay, —NHHet,—NHR¹⁰Ay, —NHR¹⁰Het, —R¹⁰cycloalkyl, —R¹⁰Ay, —R¹⁰Het, —R¹⁰O—C(O)R⁹,—R¹⁰O—C(O)Ay, —R¹⁰O—C(O)Het, —R¹⁰O—S(O)_(n)R⁹, —R¹⁰OR⁹, —R¹⁰C(O)R⁹,—R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(O)NR⁷Ay, —R¹⁰C(O)NHR¹⁰Het,—R¹⁰C(S)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹, —R¹⁰SO₂NR⁹R¹¹,—R¹⁰SO₂NHCOR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰NHC(NH)NR⁹R¹¹, cyano, nitro andazido;

[0292] or two adjacent R¹ groups together with the carbon atoms to whichthey are bonded form a cycloalkyl or a 5- or 6-membered heterocyclicgroup containing 1 or 2 heteroatoms;

[0293] each R⁷ and R⁸ are the same or different and are independentlyselected from the group consisting of H, alkyl, alkenyl, cycloalkyl,cycloalkenyl, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁹R¹¹, —C(S)NR⁹R¹¹, —C(NH)NR⁹R¹¹,—SO₂R¹⁰, —SO₂NR⁹R¹¹, —R¹⁰cycloalkyl, —R¹⁰OR⁹, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹,—R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R¹⁰,—R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂NHCOR⁹, —R¹⁰NR⁹R¹¹, —R¹⁰NHCOR⁹, —R¹⁰NHSO₂R⁹ and—R¹⁰NHC(NH)NR⁹R¹¹;

[0294] each R⁹ and R¹¹ are the same or different and are independentlyselected from the group consisting of H, alkyl, cycloalkyl,—R¹⁰cycloalkyl, —R¹⁰OH, —R¹⁰(OR¹⁰)_(w) wherein w is 1-10, and—R¹⁰NR¹⁰R¹⁰;

[0295] each R¹⁰ is the same or different and is independently selectedfrom the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl andcycloalkenyl;

[0296] Ay is aryl;

[0297] Het is a 5- or 6-membered heterocyclic or heteroaryl group;

[0298] Y is N;

[0299] R² is selected from the group consisting of halo, alkyl, alkenyl,cycloalkyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Het,—S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸, —NHHet,—NHR¹⁰Ay, —NHR¹⁰Het, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay;

[0300] n is 0, 1 or 2;

[0301] R³ and R⁴ are the same or different and are each independentlyselected from the group consisting of H, halo, alkyl, alkenyl,cycloalkyl, Ay, Het, —OR⁷, —OAy, —C(O)R⁷, C(O)Ay, —CO₂R⁷, —CO₂Ay,—SO₂NHR⁹, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Het, —R¹⁰cycloalkyl, —R¹⁰OR⁷,—R¹⁰OAy, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay;

[0302] Ring A is a 5-10 membered heterocyclic or heteroaryl group;

[0303] q is 0, 1, 2, 3, 4 or 5;

[0304] each R⁵ is the same or different and is independently selectedfrom the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OR¹⁰Ay, —OHet, —OR¹⁰Het, —C(O)R⁹,—C(O)Ay, —C(O)Het, —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(O)NHR¹⁰Het,—C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —S(O)_(n)R⁹, —S(O)₂NR⁷R⁸,—S(O)₂NR⁷Ay, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay, —NHR¹⁰Het,—R¹⁰cycloalkyl, —R¹⁰Het, —R¹⁰OR⁹, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹,—R¹⁰C(O)NR⁷Ay, —R¹⁰C(O)NHR¹⁰Het, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹,—R¹⁰SO₂R⁹, —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂NHCOR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay,—R¹⁰NHC(NH)NR⁹R¹¹, cyano, nitro and azido; and

[0305] M¹ is Li, Mg-halide or cerium-halide, wherein halide is halo.

[0306] Generally, the process for preparing compounds of formula (I)wherein Y is N comprises the following steps:

[0307] (a) reacting a compound of formula (XIII) with a compound offormula (XVIII) to prepare a compound of formula (XIX);

[0308] (b) oxidizing the compound of formula (XIX) to prepare a compoundof formula (XX); and

[0309] (c) reacting a compound of formula (XX) with a compound offormula (X) followed by oxidative aromatization to prepare a compound offormula (I).

[0310] More specifically, a compound of formula (I) can be prepared byreacting a compound of formula (XX) with a compound of formula (X)followed by oxidative aromatization.

[0311] wherein all variables are as defined above in connection withScheme 3.

[0312] The condensation is conveniently carried out by treating thecompound of formula (XX) with a compound of formula (X) in an inertsolvent, optionally in the presence of a base. The reaction may beheated to 50-150° C. or performed at ambient temperature. Suitable inertsolvents include lower alcohols such as, for example, methanol, ethanol,isopropanol and the like. The base is typically sodium alkoxide,potassium carbonate, or an amine base such as triethylamine. In anotherembodiment, the solvent is N,N-dimethylformamide and the base ispotassium carbonate, or an amine base such as triethylamine. Thereaction produces a dihydropyrimidine intermediate.

[0313] Conveniently in the same reaction vessel, the dihydropyrimidineintermediate may be oxidized to a compound of formula (I) by theaddition of an oxidizing agent. The reaction may be heated to 50-150° C.or performed at ambient temperature. Typically, the oxidizing agent isoxygen (O₂), palladium on carbon,2,3-dichloro-5,6-dicyano-1,4-benzoquinone, or the like.

[0314] A compound of formula (XX) may be conveniently prepared byoxidation of a compound of formula (XIX).

[0315] wherein all variables are as defined above in connection withScheme 3.

[0316] Suitable oxidizing agents for the oxidation of compounds offormula (XIX) include but are not limited to manganese dioxide, and thelike. The oxidation is typically carried out in an inert solvent such asfor example, dichloromethane, chloroform, N,N-dimethylformamide, ether,and the like.

[0317] A compound of formula (XIX) may be conveniently prepared byreacting a compound of formula (XIII) with a compound of formula(XVIII).

[0318] wherein M¹ is a metal such as for example, lithium, magnesium(II)halides, cerium(III) halides, and the like and all other variables areas defined above in connection with Scheme 3.

[0319] Compounds of formula (XIII) may be purchased from commercialsources or prepared by methods known to one skilled in the art. Thecompounds of formula (XIII) may be prepared using the methods describedin connection with Schemes 1 and 2 above.

[0320] In addition to the foregoing process for preparing certaincompounds of formula (I), the present invention also provides certainintermediate compounds for use in the preparation of such compounds offormula (I) according to the foregoing process. Such intermediates aredescribed in Scheme 3 above.

[0321] A compounds of formula (I) wherein Y is CH or N, may beconveniently prepared by a process outlined in Scheme 4 below.

[0322] wherein:

[0323] p is 0, 1, 2, 3 or 4;

[0324] each R¹ is the same or different and is independently selectedfrom the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OR¹⁰Ay, —OHet, —OR¹⁰Het, —C(O)R⁹,—C(O)Ay, —C(O)Het, —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(O)NHR¹⁰Ay,—C(O)NHR¹⁰Het, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —S(O)_(n)R⁹,—S(O)_(n)Ay, —S(O)_(n)Het, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —NR⁷R⁸, —NR⁷Ay,—NHHet, —NHR¹⁰Ay, —NHR¹⁰Het, —R¹⁰cycloalkyl, —R¹⁰Ay, —R¹⁰Het,—R¹⁰O—C(O)R⁹, —R¹⁰O—C(O)Ay, —R¹⁰O—C(O)Het, —R¹⁰O—S(O)_(n)R⁹, —R¹⁰OR⁹,—R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(O)NR⁷Ay, —R¹⁰C(O)NHR¹⁰Het,—R¹⁰C(S)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹, —R¹⁰O₂NR⁹R¹¹, —R¹⁰SO₂NHCOR⁹,—R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰NHC(NH)NR⁹R¹¹, cyano, nitro and azido;

[0325] or two adjacent R¹ groups together with the carbon atoms to whichthey are bonded form a cycloalkyl or a 5- or 6-membered heterocyclicgroup containing 1 or 2 heteroatoms;

[0326] each R⁷ and R⁸ are the same or different and are independentlyselected from the group consisting of H, alkyl, alkenyl, cycloalkyl,cycloalkenyl, —C(O)R⁹, —CO₂R⁹, —C(O) NR⁹R¹¹, —C(S)NR⁹R¹¹, —C(NH)NR⁹R¹¹,—SO₂R¹⁰, —SO₂NR⁹R¹¹, —R¹⁰cycloalkyl, —R¹⁰OR⁹, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹,—R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R¹⁰,—R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂NHCOR⁹, —R¹⁰NR⁹R¹¹, —R¹⁰NHCOR⁹, —R¹⁰NHSO₂R⁹ and—R¹⁰NHC(NH)NR⁹R¹¹;

[0327] each R⁹ and R¹¹ are the same or different and are independentlyselected from the group consisting of H, alkyl, cycloalkyl,—R¹⁰cycloalkyl, —R¹⁰OH, —R¹⁰(OR¹⁰)_(w) wherein w is 1-10, and—R¹⁰NR¹⁰R¹⁰;

[0328] each R¹⁰ is the same or different and is independently selectedfrom the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl andcycloalkenyl;

[0329] Ay is aryl;

[0330] Het is a 5- or 6-membered heterocyclic or heteroaryl group;

[0331] Y is N or CH;

[0332] R² is selected from the group consisting of halo, alkyl, alkenyl,cycloalkyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Het,—S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸, —NHHet,—NHR¹⁰Ay, —NHR¹⁰Het, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay;

[0333] n is 0, 1 or 2;

[0334] R³ and R⁴ are the same or different and are each independentlyselected from the group consisting of H, halo, alkyl, alkenyl,cycloalkyl, Ay, Het, —OR⁷, —OAy, —C(O)R⁷, C(O)Ay, —CO₂R⁷, —CO₂Ay,—SO₂NHR⁹, —NR⁷R¹¹, —NR⁷Ay, —NHHet, —NHR¹⁰Het, —R¹⁰cycloalkyl, —R¹⁰OR⁷,—R¹⁰OAy, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay;

[0335] Ring A is a 5-10 membered heterocyclic or heteroaryl group;

[0336] q is 0, 1, 2, 3, 4 or 5;

[0337] each R⁵ is the same or different and is independently selectedfrom the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OR¹⁰Ay, —OHet, —OR¹⁰Het, —C(O)R⁹,—C(O)Ay, —C(O)Het, —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(O)NHR¹⁰Het,—C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —S(O)_(n)R⁹, —S(O)₂NR⁷R⁸,—S(O)₂NR⁷Ay, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay, —NHR¹⁰Het,—R¹⁰cycloalkyl, —R¹⁰Het, —R¹⁰OR⁹, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹,—R¹⁰C(O)NR⁷Ay, —R¹⁰C(O)NHR¹⁰Het, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹,—R¹⁰SO₂R⁹, —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂NHCOR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay,—R¹⁰NHC(NH)NR⁹R¹¹, cyano, nitro and azido;

[0338] X¹ is chloro, bromo, or iodo; and

[0339] M² is -B(OH)₂, -B(ORa)₂, -B(Ra)₂, —Sn(Ra)₃, Zn-halide, ZnRa, orMg-halide where Ra is alkyl or cycloalkyl and halide is halo.

[0340] Generally, the process for preparing compounds of formula (I)(all formulas and variables having been defined above in connection withScheme 4), comprises the following steps:

[0341] a) halogenating a compound of formula (VI) to prepare a compoundof formula (XXII); and

[0342] b) reacting a compound of formula (XXII) with a compound offormula (XXIV) to prepare a compound of formula (I).

[0343] More specifically, a compound of formula (I) wherein Y is N or CHcan be prepared by reacting a compound of formula (XXII) with a compoundof formula (XXIV).

[0344] wherein all variables are as defined above in connection withScheme 4.

[0345] The reaction may be carried out in an inert solvent, in thepresence of a palladium (O) or nickel (O) catalyst. The reaction mayoptionally be heated to about 50-150° C. Typically the reaction isperformed by reacting equimolar amounts of a compound of formula (XXII)with a heteroaryl-metal compound of formula (XXIV), but the reaction mayalso be performed in the presence of an excess of compound of theformula (XXIV). The palladium or nickel catalyst is typically present in1-10 mol % compared to the compound of formula (XXII). Examples ofsuitable palladium catalysts include but are not limited to,tetrakis(triphenylphosphine)palladium (O),dichlorobis(triphenylphosphine)palladium(II),tris(dibenzylideneacetone)dipalladium (O), andbis(diphenylphosphinoferrocene)palladium (II) dichloride. Suitablesolvents include but are not limited to, N,N-dimethylformamide, toluene,tetrahydrofuran, dioxane, and 1-methyl-2-pyrrolidinone. When theheteroaryl-metal compound of formula (XXIV) is an arylboronic acid orester or an arylborinate the reaction is more conveniently carried outby adding a base in a proportion equivalent to, or greater than, that ofthe compound of formula (XXIV). Heteroaryl-metal compounds of formula(XXIV) may be obtained from commercial sources or prepared either asdiscreet isolated compounds or generated in situ using methods known toone skilled in the art. (Suzuki, A. J. Organomet. Chem. 1999, 576, 147;Stille, J. Angew. Chem. Int. Ed. Engl. 1986, 25, 508; Snieckus, V. J.Org. Chem. 1995, 60, 292.)

[0346] A compound of formula (XXII) can be prepared from a compound offormula (VI) by a halogenation procedure.

[0347] wherein all variables are as defined above in connection withScheme 4.

[0348] Typically, the halogenation reaction is carried out by subjectingthe compound of formula (VI) to a halogenating agent in a suitablesolvent. Suitable halogenating agents include but are not limited to,iodine, N-bromosuccinimide, trialkylammonium tribromides, bromine,N-chlorosuccinimide, N-iodosuccinimide, iodine, iodine monochloride, andthe like. Suitable solvents include, for example, N,N-dimethylformamide,tetrahydrofuran, dioxane, 1-methyl-2-pyrrolidinone, carbontetrachloride, toluene, dichloromethane, diethyl ether, and the like.

[0349] In addition to the foregoing process for preparing certaincompounds of formula (I), the present invention also provides certainintermediate compounds for use in the preparation of such compounds offormula (I) according to the foregoing process. Such intermediates aredescribed in Scheme 4 above.

[0350] In another embodiment, a compound of formula (I) may beconveniently prepared by a process outlined in Scheme 5 below

[0351] wherein:

[0352] p is 0, 1, 2, 3 or 4;

[0353] each R¹ is the same or different and is independently selectedfrom the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OR¹⁰Ay, —OHet, —OR¹⁰Het, —C(O)R⁹,—C(O)Ay, —C(O)Het, —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(O)NHR¹⁰Ay,—C(O)NHR¹⁰Het, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —S(O)_(n)R⁹,—S(O)_(n)Ay, —S(O)_(n)Het, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —NR⁷R⁸, —NR⁷Ay,—NHHet, —NHR¹⁰Ay, —NHR¹⁰Het, —R¹⁰cycloalkyl, —R¹⁰Ay, —R¹⁰Het,—R¹⁰O—C(O)R⁹, —R¹⁰O—C(O)Ay, —R¹⁰O—C(O)Het, —R¹⁰O—S(O)_(n)R⁹, —R¹⁰OR⁹,—R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(O)NR⁷Ay, —R¹⁰C(O)NHR¹⁰Het,—R¹⁰C(S)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹, —R¹⁰SO₂NR⁹R¹¹,—R¹⁰SO₂NHCOR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰NHC(NH)NR⁹R¹¹, cyano, nitro andazido;

[0354] or two adjacent R¹ groups together with the carbon atoms to whichthey are bonded form a cycloalkyl or a 5- or 6-membered heterocyclicgroup containing 1 or 2 heteroatoms;

[0355] each R⁷ and R⁸ are the same or different and are independentlyselected from the group consisting of H, alkyl, alkenyl, cycloalkyl,cycloalkenyl, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁹R¹¹, —C(S)NR⁹R¹¹, —C(NH)NR⁹R¹¹,—SO₂R¹⁰, —SO₂NR⁹R¹¹, —R¹⁰cycloalkyl, —R¹⁰OR⁹, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹,—R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R¹⁰,—R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂NHCOR⁹, —R¹⁰NR⁹R¹¹, —R¹⁰NHCOR⁹, —R¹⁰NHSO₂R⁹ and—R¹⁰NHC(NH)NR⁹R¹¹;

[0356] each R⁹ and R¹¹ are the same or different and are independentlyselected from the group consisting of H, alkyl, cycloalkyl,—R¹⁰cycloalkyl, —R¹⁰OH, —R¹⁰(OR¹⁰)_(w) wherein w is 1-10, and—R¹⁰NR¹⁰R¹⁰;

[0357] each R¹⁰ is the same or different and is independently selectedfrom the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl andcycloalkenyl;

[0358] Ay is aryl;

[0359] Het is a 5- or 6-membered heterocyclic or heteroaryl group;

[0360] Y is N or CH;

[0361] R² is selected from the group consisting of halo, alkyl, alkenyl,cycloalkyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Het,—S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸, —NHHet,—NHR¹⁰Ay, —NHR¹⁰Het, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay;

[0362] n is 0, 1 or 2;

[0363] R³ and R⁴ are the same or different and are each independentlyselected from the group consisting of H, halo, alkyl, alkenyl,cycloalkyl, Ay, Het, —OR⁷, —OAy, —C(O)R⁷, C(O)Ay, —CO₂R⁷, —CO₂Ay,—SO₂NHR⁹, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Het, —R¹⁰cycloalkyl, —R¹⁰OR⁷,—R¹⁰OAy, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay;

[0364] Ring A is a 5-10 membered heterocyclic or heteroaryl group;

[0365] q is 0, 1, 2, 3, 4 or 5;

[0366] each R⁵ is the same or different and is independently selectedfrom the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OR¹⁰Ay, —OHet, —OR¹⁰Het, —C(O)R⁹,—C(O)Ay, —C(O)Het, —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(O)NHR¹⁰Het,—C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —S(O)_(n)R⁹, —S(O)₂NR⁷R⁸,—S(O)₂NR⁷Ay, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay, —NHR¹⁰Het,—R¹⁰cycloalkyl, —R¹⁰Het, —R¹⁰OR⁹, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹,—R¹⁰C(O)NR⁷Ay, —R¹⁰C(O)NHR¹⁰Het, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹,—R¹⁰SO₂R⁹, —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂NHCOR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay,—R¹⁰NHC(NH)NR⁹R¹¹, cyano, nitro and azido; and

[0367] Z- is a counter ion.

[0368] Generally, a compound of formula (I) may be prepared by a processcomprising the steps of:

[0369] (a) reacting a compound of formula (XXV) with an alkyne offormula (XXVI) followed by desilylation to give a compound of formula(XXVII);

[0370] (b) reacting the compound of formula (XXVII) with a compound offormula (XXVIII) to prepare a compound of formula (XXIX);

[0371] (c) reacting the compound of formula (XXIX) with a1-aminopyridinium salt of formula (XXX) to prepare a compound of formula(I).

[0372] The order of the foregoing steps is not critical to the processand as such these steps may be carried out in any suitable orderaccording to the skill in the art. More specifically, a compound offormula (I) can be prepared by reacting a compound of formula (XXIX)with a 1-aminopyridinium salt of formula (XXX) to prepare a compound offormula (I).

[0373] wherein all variables are as defined above in connection withScheme 5.

[0374] Cycloaddition reactions such as these are commonly known as [3+2]dipolar cycloaddition reactions. Conveniently the reaction may becarried out by mixing the reactants (i.e., compounds of formula (XXVII)and (XXVIII)), in equimolar amounts, in an inert solvent and adding asuitable base. The mixture is then stirred at between 20-100° C. untilthe reaction is judged complete by the disappearance of one of thereactants. Suitable solvents include but are not limited toacetonitrile, dioxane, tetrahydrofuran, dimethylformamide and the like.Suitable bases include non-nucleophilic amines such as1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene,1,4-diazabicyclo[2.2.2]octane and the like. Compounds of formula (XXX)are aminated pyridine derivatives and are either commercially availableor can be conveniently prepared by reacting a suitable pyridine with anaminating reagent such as O-(mesitylsulfonyl)hydroxylamine,O-(diphenylphosphinyl)hydroxylamine, hydroxylamine-O-sulfonic acid andthe like.

[0375] Alkynyl compounds of formula (XXIX) are either known compounds orcan be prepared by methods described in the literature or known to thoseskilled in the art of organic synthesis.

[0376] In addition to the foregoing process for preparing certaincompounds of formula (I), the present invention also provides certainintermediate compounds for use in the preparation of such compounds offormula (I) according to the foregoing process. Such intermediates aredescribed in Scheme 5 above.

[0377] In a further embodiment, a compound of formula (I) may beconveniently prepared by a process outlined in Scheme 6 below

[0378] wherein:

[0379] p is 0, 1, 2, 3 or 4;

[0380] each R¹ is the same or different and is independently selectedfrom the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OR¹⁰Ay, —OHet, —OR¹⁰Het, —C(O)R⁹,—C(O)Ay, —C(O)Het, —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(O)NHR¹⁰Ay,—C(O)NHR¹⁰Het, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —S(O)_(n)R⁹,—S(O)_(n)Ay, —S(O)_(n)Het, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —NR⁷R⁸, —NR⁷Ay,—NHHet, —NHR¹⁰Ay, —NHR¹⁰Het, —R¹⁰cycloalkyl, —R¹⁰Ay, —R¹⁰Het,—R¹⁰O—C(O)R⁹, —R¹⁰O—C(O)Ay, —R¹⁰O—C(O)Het, —R¹⁰O—S(O)_(n)R⁹, —R¹⁰OR⁹,—R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(O)NR⁷Ay, —R¹⁰C(O)NHR¹⁰Het,—R¹⁰C(S)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹, —R¹⁰SO₂NR⁹R¹¹,—R¹⁰SO₂NHCOR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰NHC(NH)NR⁹R¹¹, cyano, nitro andazido;

[0381] or two adjacent R¹ groups together with the carbon atoms to whichthey are bonded form a cycloalkyl or a 5- or 6-membered heterocyclicgroup containing 1 or 2 heteroatoms;

[0382] each R⁷ and R⁸ are the same or different and are independentlyselected from the group consisting of H, alkyl, alkenyl, cycloalkyl,cycloalkenyl, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁹R¹¹, —C(S)NR⁹R¹¹, —C(NH)NR⁹R¹¹,—SO₂R¹⁰, —SO₂NR⁹R¹¹, —R¹⁰cycloalkyl, —R¹⁰OR⁹, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹,—R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R¹⁰,—R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂NHCOR⁹, —R¹⁰NR⁹R¹¹, —R¹⁰NHCOR⁹, —R¹⁰NHSO₂R⁹ and—R¹⁰NHC(NH)NR⁹R¹¹;

[0383] each R⁹ and R¹¹ are the same or different and are independentlyselected from the group consisting of H, alkyl, cycloalkyl,—R¹⁰cycloalkyl, —R¹⁰OH, —R¹⁰(OR¹⁰)_(w) wherein w is 1-10, and—R¹⁰NR¹⁰R¹⁰;

[0384] each R¹⁰ is the same or different and is independently selectedfrom the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl andcycloalkenyl;

[0385] Ay is aryl;

[0386] Het is a 5- or 6-membered heterocyclic or heteroaryl group;

[0387] Y is N or CH;

[0388] R² is selected from the group consisting of halo, alkyl, alkenyl,cycloalkyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet, —OR¹⁰Het,—S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸, —NHHet,—NHR¹⁰Ay, —NHR¹⁰Het, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay;

[0389] n is 0, 1 or 2;

[0390] R³ and R⁴ are the same or different and are each independentlyselected from the group consisting of H, halo, alkyl, alkenyl,cycloalkyl, Ay, Het, —OR⁷, —OAy, —C(O)R⁷, C(O)Ay, —CO₂R⁷, —CO₂Ay,—SO₂NHR⁹, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Het, —R¹⁰cycloalkyl, —R¹⁰OR⁷,—R¹⁰OAy, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay;

[0391] Ring A is a 5-10 membered heterocyclic or heteroaryl group;

[0392] q is 0, 1, 2, 3, 4 or 5;

[0393] each R⁵ is the same or different and is independently selectedfrom the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OR¹⁰Ay, —OHet, —OR¹⁰Het, —C(O)R⁹,—C(O)Ay, —C(O)Het, —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(O)NHR¹⁰Het,—C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —S(O)_(n)R⁹, —S(O)₂NR⁷R⁸,—S(O)₂NR⁷Ay, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay, —NHR¹⁰Het,—R¹⁰cycloalkyl, —R¹⁰Het, —R¹⁰OR⁹, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹,—R¹⁰C(O)NR⁷Ay, —R¹⁰C(O)NHR¹⁰Het, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹,—R¹⁰SO₂R⁹, —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂NHCOR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay,—R¹⁰NHC(NH)NR⁹R¹¹, cyano, nitro and azido; and

[0394] Z- is a counter ion.

[0395] Generally, a compound of formula (I) can be prepared by a processcomprising the steps of:

[0396] (a) reacting a compound of formula (XXXI) with an alkyne offormula (XXXII) to prepare a compound of formula (XXXIII);

[0397] (b) reacting the compound of formula (XXXIII) with a1-aminopyridinium salt of formula (XXX) to prepare a compound of formula(XXXIV);

[0398] (c) oxidizing the compound of formula (XXXIV) to prepare acompound of formula (XXXV);

[0399] (d) brominating the compound of formula (XXXV) to prepare acompound of formula (XXXVI); and

[0400] (e) treating the compound of formula (XXXVI) with a ring formingreagent to prepare a compound of formula (I).

[0401] More specifically, a compound of formula (I) can be prepared byreacting the compound of formula (XXXVI) with a suitable ring formingreagent.

[0402] wherein all variables are as defined in connection with Scheme 6.

[0403] Reactions of a alpha-halocarbonyl component with a ring formingreagent are well known to those skilled in the art of heterocyclicsynthesis (Heterocyclic Chemistry 4^(th) Ed., J. A. Joule and K. Mills,Blackwell Science 2000 etc.). Examples of such reactions include, butare not limited to, reaction of the alpha-halocarbonyl component withthioformamide or higher thioamides to give thiazoles, amidines to giveimidazoles, amides to give oxazoles, etc. Examples of suitable ringforming agents include but are not limited to thiourea, acetamide andbenzamidine.

[0404] A compound of formula (XXXVI) can be prepared by bromination of acompound of formula (XXXV).

[0405] wherein all variables are as defined above in connection withScheme 6.

[0406] Bromination can be carried out using any of several brominationmethods known to those skilled in the art of organic synthesis.Treatment of compound of formula (XXXV) with bromine in acetic acid isan example of one particular bromination method.

[0407] A compound of formula (XXXV) can be prepared by oxidation of acompound of formula (XXXIV).

[0408] wherein all variables are as defined above in connection withScheme 6.

[0409] Suitable oxidizing agents include but are not limited to,manganese dioxide, and the like, in an inert solvent Suitable inertsolvents include but are not limited to, dichloromethane, chloroform,N1N-dimethylformamide, ether, and the like.

[0410] A compound of formula (XXXIV) can be prepared by reacting acompound of formula (XXXIII) with a 1-aminopyridinium salt of formula(XXX).

[0411] wherein all variables are as defined above in connection withScheme 6.

[0412] Cycloaddition reactions such as these are commonly known as [3+2]dipolar cycloaddition reactions. Conveniently the reaction may becarried out by mixing the reactants (XXXIII) and (XXX), in equimolaramounts, in an inert solvent and adding a suitable base. The mixture isthen stirred at between 20-100° C. until the reaction is judged completeby the disappearance of one of the reactants. Suitable solvents includebut are not limited to acetonitrile, dioxane, tetrahydrofuran,dimethylformamide and the like. Suitable bases include non-nucleophilicamines such as 1,8-diazabicyclo[5.4.0]undec-7-ene,1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane and thelike.

[0413] Acetylenic compounds of formula (XXXIII) are either knowncompounds or can be prepared by methods described in the literature orare known to those skilled in the art of organic synthesis.

[0414] In addition to the foregoing process for preparing certaincompounds of formula (I), the present invention also provides certainintermediate compounds for use in the preparation of such compounds offormula (I) according to the foregoing process. Such intermediates aredescribed in Scheme 6 above.

[0415] Any of the processes described above may optionally comprise thefurther step of converting a compound of formula (I) into apharmaceutically acceptable salt, solvate or physiologically functionalderivative thereof. Processes for such conversion are well known in theart.

[0416] As will be apparent to those skilled in the art, the compounds offormula (I) may be converted to other compounds of formula (I) usingtechniques well known in the art For example, one method of converting acompound of formula (I) to another compound of formula (I) comprises a)oxidizing the compound of formula (I-A) to prepare a compound of formula(I-B) and then b) optionally reacting a compound of formula (I-B) withan oxygen or amine nucleophile of formula R², wherein R² is —NR⁷R⁸,—OR¹¹, Het attached through N, —NHHet, NHR¹⁰Het, OHet and —OR¹⁰Het toproduce a compound of formula (I) wherein R² is —NR⁷R⁸, —OR⁷, Hetattached through N, —NHHet, NHR¹⁰Het, OHet and —OR¹⁰Het.

[0417] wherein n′ is 1 or 2;

[0418] R² is selected from the group consisting of —NR⁷R⁸, —OR⁷, Hetlinked through N, —NHHet, —NHR¹⁰Het, —OHet, and —OR¹⁰Het; and

[0419] all other variables are as defined according to any processdescribed above.

[0420] More specifically, a compound of formula (I) wherein R² isselected from the group consisting of —NR⁷R⁸, —OR⁷, Het linked throughN, —NHHet, —NHR¹⁰Het, —OHet, and —OR¹⁰Het, can be prepared by reacting acompound of formula (I-B) (i.e., a compound of formula (I) wherein R² is—S(O)_(n′)R⁹ where n′ is 1 or 2) with an oxygen or amine nucleophile offormula R², wherein R² is —NR⁷R⁸, —OR⁷, Het linked through N, —NHHet,—NHR¹⁰Het, —OHet, and —OR¹⁰Het. The reaction may be carried out neat orin a suitable solvent and may be heated to 50-150° C. Typically thesolvent is a lower alcohol such as methanol, ethanol, isopropanol andthe like or solvent such as N,N-dimethylformamide or tetrahydrofuran,and the like. Optionally a base may be used to facilitate the reaction.Typically the base can be potassium carbonate, or an amine base such astriethylamine.

[0421] A compound of formula (I-B) may be conveniently prepared byreacting a compound of formula (I-A) (i.e., a compound of formula (I)wherein R² is —S(O)_(n)R⁹ where n is 0) with an oxidizing agent in aninert solvent, optionally in the presence of a base. Typically theoxidizing agent is a peracid such as 3-chloroperbenzoic acid or the likeoptionally with a base such as sodium bicarbonate. Careful monitoring ofthe stoichiometry between the oxidizing agent and the substrate allowsthe product distribution between sulfoxide (n=1), and sulfone (n=2) tobe controlled. Suitable solvents include but are not limited to,dichloromethane, chloroform and the like. If the compound of formula(I-A) contains oxidizeable nitrogens, it may be preferred to perform theoxidation under acidic conditions. Acetic acid and the like can be addedto make the solution acidic.

[0422] A compound of formula (I-A) can be prepared by methods describedabove wherein R²=SR⁹ from the reaction of a compound selected from thegroup consisting of a compound of formula (XVI), a compound of formula(IX) and a compound of formula (XX) with a compound of formula (X-A)(i.e., the compound of formula (X) wherein R² is —SR⁹). The requisitecompound of formula (X-A) can be obtained from commercial sources orprepared by methods known to one skilled in the art.

[0423] Another particularly useful method for converting a compound offormula (I) to another compound of formula (I) comprises reacting acompound of formula (I-C) (i.e., a compound of formula (I) wherein R² isfluoro) with an amine nucleophile (including unsubstituted andsubstituted amines, heterocycles and heteroaryls, particularly thosebound through N), and optionally heating the mixture to 50-150° C. toprepare a compound of formula (I-D) (i.e., a compound of formula (I)wherein R² is selected from the group consisting of Het, —NR⁷R⁸, —NHHet,—NHR¹⁰Ay and —NHR¹⁰Het).

[0424] wherein R^(2′) is selected from the group consisting of Het,—NR⁷R⁸, —NHHet, —NHR¹⁰Ay and —NHR¹⁰Het, and

[0425] all other variables are as defined in any process describedabove.

[0426] This procedure may be carried out by mixing a compound of formula(I-C) in a neat amine, or in a suitable solvent with an excess of anamine to produce a compound of formula (I-D). Typically the solvent is alower alcohol such as methanol, ethanol, isopropanol and the like. Othersuitable solvents may include N,N-dimethylformamide,1-methyl-2-pyrrolidine and the like.

[0427] As a further example, a compound of formula (I-E) may beconverted to a compound of formula (I-F) using either of two methods.

[0428] wherein M³ is B(OH)₂, B(ORa)₂, B(Ra)₂, Sn(Ra)₃, Zn-halide; Zn—Raor Mg-halide, Rg is Ay or Het, and all other variables are as defined inany process described above.

[0429] Such method can be carried out using the reaction and conditionsdescribed above in connection with Scheme 1 for the conversion of acompound of formula (VII-A) to a compound of formula (VII). Thus, thepresent invention provides a process for converting a compound offormula (I-E) to a compound of formula (I-F) which comprises either: (1)replacing a halogen of the compound of formula (I-E) with an amine; or(2) coupling the compound of formula (I-E) with a metal compound of theformula Rg-M³ where M³ is B(OH)₂, B(ORa)₂, B(Ra)₂, Sn(Ra)₃, Zn-halide;Zn—Ra or Mg-halide.

[0430] As a further example, a compound of formula (I-G) (i.e., acompound of formula (I) wherein q is 1 or more and at least one R⁵ is—O-methyl) may be converted to a compound of formula (I-H) (i.e., acompound of formula (I) wherein q is 1 or more and at least one R⁵ is—OH) using conventional demethylation techniques. Additionally, acompound of formula (I-H) may optionally be converted to a compound offormula (I-J) (i.e., a compound of formula (I) wherein q is 1 or moreand at least one R⁵ is —OR¹⁰). For example, the foregoing conversionsare represented schematically as follows:

[0431] wherein q′ is 0-4; Me is methyl and all other variables aredefined according to any process described above.

[0432] The demethylation reaction may be carried out by treating acompound of formula (I-G) in a suitable solvent with a Lewis acid at atemperature of −78° C. to room temperature, to produce a compound offormula (I-H). Typically the solvent is an inert solvent such asdichloromethane, chloroform, acetonitrile, toluene or the like. TheLewis acid may be boron tribromide, trimethylsilyl iodide or the like.

[0433] Optionally, a compound of formula (I-H) may be further convertedto a compound of formula (I-J) by an alkylation reaction. The alkylationreaction may be carried out by treating a compound of formula (I-H) insuitable solvent with an alkyl halide of formula R¹⁰-halo where R¹⁰ isas defined above, to form another compound of formula (I-J). Thereaction is preferably carried out in the presence of a base and withoptionally heating to 50-200° C. The reaction may be carried out insolvents such as N,N-dimethylformamide, dimethylsulfoxide and the like.Typically the base is potassium carbonate, cesium carbonate, sodiumhydride or the like. Additionally, as will be apparent to those skilledin the art, the alkylation reaction can be carried out under Mitsunobuconditions.

[0434] The foregoing reaction method can also be used to convert acompound of formula (I) wherein at least one R¹ is —OMe to a compound offormula (I) wherein at least one R¹ is —OR¹⁰. In another embodiment, theforegoing methods are employed to make the same conversion when R³ or R⁴is —OMe, to prepare a compound of formula (I) wherein R³ or R⁴ is —OH ora compound of formula (I) wherein R³ or R⁴ is —OR¹⁰.

[0435] As a further example of methods for converting a compound offormula (I) to another compound of formula (I), a compound of formula(I-K) (i.e., a compound of formula (I) wherein q is 1 or more and atleast one R¹ is halo) may be converted to a compound of formula (I-L)(i.e., a compound of formula (I) wherein q is 1 or more and at least oneR⁵ is Ay, Het or a nitrogen-linked substituent). For example, theconversion of a compound of formula (I-K) to a compound of formula (I-L)is shown schematically below.

[0436] wherein:

[0437] q′ is 0-4;

[0438] R^(5′) is selected from the group consisting of Ay, —NHR¹⁰Ay,—NR⁷Ay, Het, —NHHet, —NHR¹⁰Het, and —NR⁷R⁸;

[0439] M⁴ is selected from the group consisting of -B(OH)₂, -B(ORa)₂,-B(Ra)₂, and —Sn(Ra)₂ wherein Ra is alkyl or cycloalkyl; and

[0440] all other variables are as defined according to any processdescribed above.

[0441] The conversion of compounds of formula (I-K) to compounds offormula (I-L) is carried out by heating with a compound of formulaH-R^(5′) or coupling the compound of formula (I-K) with a compound offormula R^(5′)-M⁴, where M⁴ is -B(OH)₂, -B(ORa)₂, -B(Ra)₂, —Sn(Ra)₂wherein Ra is alkyl or cycloalkyl. The reaction may be carried out in aninert solvent, in the presence of a palladium (O) source. The reactionmay optionally be heated to 50-150° C. Preferably the reaction isperformed by reacting equimolar amounts of a compound of formula (I-K)with a compound of formula R^(5′)-M⁴. The reaction may also be performedin the presence of an excess R^(5′)-M⁴. The palladium (O) catalyst ispreferably present in 1-25 mol % compared to the compound of formula(I-K). Examples of suitable palladium catalysts include but are notlimited to, tetrakis(triphenylphosphine)palladium (O),dichlorobis(triphenylphosphine)palladium(II), andbis(diphenylphosphinoferrocene)palladium (II) dichloride. Suitablesolvents include but are not limited to, N,N-dimethylformamide, toluene,tetrahydrofuran, dioxane, and 1-methyl-2-pyrrolidinone. When thecompound of formula R^(5′)-M⁴ is a boronic acid or ester or a borinatethe reaction is more conveniently carried out by adding a base in aproportion equivalent to, or greater than, that of the compound offormula R^(5′)-M⁴. A compound of formula R^(5′)-M⁴ may be obtained fromcommercial sources or prepared either as discreet isolated compound orgenerated in situ using methods known to one skilled in the art.(Suzuki, A. J. Organomet. Chem. 1999, 576,147; Stille, J. Angew. Chem.Int. Ed. Engl. 1986, 25, 508; Snieckus, V. J. Org. Chem. 1995, 60, 292.)

[0442] In yet another example, a compound of formula (I-K) (i.e., acompound of formula (I) wherein q is 1 or more and at least one R⁵ ishalo) is converted to a compound of formula (I-N) (i.e., a compound offormula (I) wherein q is 1 or more and at least one R⁵ is —NH₂).Optionally, a compound of formula (I-N) may then be converted to acompound of formula (I-O) (i.e., a compound of formula (I) wherein q is1 or more and at least one R⁵ is —NR⁷R⁸ where R⁷ and R⁸ are not both H).For example, the foregoing conversions are represented schematically asfollows:

[0443] wherein q′ is 0-4, and all other variables are defined accordingto any process described above.

[0444] The process of converting a compound of formula (I-K) to acompound of formula (I-N) is carried out by reacting a compound offormula (I-K) with an imine in the presence of a palladium (O) source, abase and a suitable ligand, followed by hydrolysis to give a compound offormula (I-N). See J. Wolfe, et al., Tetrahedron Letters 38:6367-6370(1997). Typically the imine is benzophenoneimine, the palladium (O)source is tris(dibenzylideneacetone)dipalladium(O), the base is sodiumtert-butoxide and the ligand isracemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl. Suitable solventsinclude N,N-dimethylformamide and the like.

[0445] Reaction of a compound of formula (I-N) with compound of formulaR⁷-halogen in a suitable solvent in the presence of base, optionallywith heating may be used to prepare compounds of formula (I-O).Typically the base is triethylamine or pyridine and the solvent isN,N-dimethylformamide and the like. Other transformations well known tothose skilled in the art for use with anilines may be used to convert acompound of formula (I-N) to a compound of formula (I-O).

[0446] Additional compounds of formula (I-O) can be obtained byreductive amination of compounds of formula (I-N) with ketones oraldehydes. See, A. Abdel-Magid, et al., J. Org. Chem. 61:3849-3862(1996). Typically a compound of formula (I-N) is treated with analdehyde or a ketone in the presence of an acid, such as acetic acid,and a reducing agent, such as sodium triacetoxyborohydride and the like,in an inert solvent such as dichloroethane and the like.

[0447] The foregoing reaction methods can also be used to convert acompound of formula (I) wherein at least one R¹ is halo to a compound offormula (I) wherein at least one R¹ is —NH₂. In another embodiment, theforegoing methods are employed to make the same conversion when R³ or R⁴is halo, to prepare a compound of formula (I) wherein R³ or R⁴ is —NH₂or a compound of formula (I) wherein R³ or R⁴ is —NR⁷R⁸ (where R⁷ and R⁸are not both H).

[0448] As previously described, another method for converting a compoundof formula (I-K) directly to a compound of formula (I-O) involvesheating a compound of formula (I-K) with a amine to thermally displacethe halogen.

[0449] In the embodiment where a compound of formula (I) is definedwhere R¹ is not located at C-7, the compound of formula (I-P) may beconverted to a compound of formula (I-Q). For example, a compound offormula (I-P) may be converted to a compound of formula (I-Q) by adeprotonation/electrophile quench protocol. For example, reaction of acompound of formula (I-P) with a base, such as n-butyllithium, followedby reacting with an electrophilic agent gives compounds of formula(I-Q).

[0450] wherein p′ is 0-2 and E is selected from halo, alkyl,R¹⁰cycloalkyl, —C(O)R⁹, —C(O)Ay, —C(O)Het, —CO₂R⁹, —C(O)NR⁷R⁸,—C(O)NR⁷Ay and —S(O)_(n)R⁹, and all other variables are as defined inconnection with any processes described above.

[0451] Electrophiles which may be used in this process include, but arenot limited to: halogens (E=iodo, bromo, chloro), alkyl halides(E=methyl, benzyl etc.); aldehydes (E=CH(OH)R¹⁰); dimethylformamide(E=CHO); dialkyl disulfide (E=SMe, SEt, S-isopropyl etc); carbon dioxide(E=CO₂H); dimethylcarbamoyl chloride (E=C(O)NMe₂) and the like.

[0452] Typically a compound of formula (I-P) in an inert solvent such astetrahydrofuran at −78° C. is treated with a nonnucleophilic base. Thisreaction is subsequently quenched by addition of an electrophile.Suitable nonnucleophilic bases include, but are not limited to,n-butyllithium, lithium diisopropylamide, lithium tetramethylpiperidideand the like.

[0453] Further, compounds of formula (I) wherein R¹ is not located atC-7, may be converted to other compounds of formula (I), by adeprotonation/electrophile quench/nucleophilic displacement protocol.For example, reaction of a compound of formula (I-P) with a base, suchas n-butyllithium, followed by quenching with an electrophilichalogenating agent gives a compound of formula (I-Q) where E is halogen,as outlined in the previous scheme. Treatment of compound of formula(I-Q), where E is halogen with a nucloephile (Z¹) in a suitable solventoptionally with heating and optionally in the presence of a base gives acompound of formula (I-R).

[0454] wherein p′ is 0-3, Z₁ is selected from the group consisting of—NHR¹⁰Ay, —NR⁷Ay, Het, —NHHet, —NHR¹⁰Het, —OR⁷, —OAy, —OR¹⁰Ay, —OHet,—OR¹⁰Het, —NR⁷R⁸, —S(O)_(n)R⁹(where n is 0), cyano and all othervariables are as defined according to any process described above.

[0455] Solvents for use in this reaction include but are not limited totetrahydrofuran, diethylether, and 1-methyl-2-pyrrolidinone. The basemay be sodium hydride, sodium-tert-butoxide, potassium carbonate or thelike.

[0456] As another example, one method of converting a compound offormula (I) to another compound of formula (I) comprises a) oxidizingthe compound of formula (I-S), where R¹ is —SR¹⁵ and R¹⁵ is alkyl,cycloalkyl or Ay and is located at C-7, to prepare a compound of formula(I-T) and then b) optionally reacting a compound of formula (I-T) with anucleophile Z₁ selected from the group consisting of —NHR¹⁰Ay, —NR⁷Ay,Het, —NHHet, —NHR¹⁰Het, —OR⁷, —OAy, —OR¹⁰Ay, —OHet, —OR¹⁰Het, —NR⁷R⁸,—S(O)_(n)R⁹ (where n is 0) and cyano, to prepare a compound of formula(I-U).

[0457] wherein p′ is 0-3; Z₁ is selected from the group consisting of—NHR¹⁰Ay, —NR⁷Ay, Het, —NHHet, —NHR¹⁰Het, —OR⁷, —OAy, —OR¹⁰Ay, —OHet,—OR¹⁰Het, —NR⁷R⁸, —S(O)_(n)R⁹ (where n is 0) and cyano; R¹⁵ is alkyl,cycloalkyl or Ay; and all other variables are as defined according toany processes described above.

[0458] Based upon this disclosure and the examples contained herein oneskilled in the art can readily convert a compound of formula (I) or apharmaceutically acceptable salt, solvate or physiologically functionalderivative thereof into another compound of formula (I), or apharmaceutically acceptable salt, solvate or physiologically functionalderivative thereof.

[0459] The present invention also provides radiolabeled compounds offormula (I) and biotinylated compounds of formula (I). Radiolabeledcompounds of formula (I) and biotinylated compounds of formula (I) canbe prepared using conventional techniques. For example, radiolabeledcompounds of formula (I) can be prepared by reacting the compound offormula (I) with tritium gas in the presence of an appropriate catalystto produce radiolabeled compounds of formula (I). In one preferredembodiment, the compounds of formula (I) are tritiated.

[0460] The radiolabeled compounds of formula (I) and the biotinylatedcompounds of formula (I) are useful in assays for the identification ofcompounds for the treatment or prophylaxis of viral infections such asherpes viral infections. Accordingly, the present invention provides anassay method for identifying compounds which have activity for thetreatment or prophylaxis of viral infections such as herpes viralinfections, which method comprises the step of specifically binding theradiolabeled compound of formula (I) or the biotinylated compounds offormula (I) to the target protein. More specifically, suitable assaymethods will include competition binding assays. The radiolabeledcompounds of formula (I) can be employed in assays according to themethods conventional in the art.

[0461] The following examples are illustrative embodiments of theinvention, not limiting the scope of the invention in any way, theinvention being defined by the claims which follow. Reagents arecommercially available or are prepared according to procedures in theliterature. Example numbers refer to those compounds listed in thetables above. ¹H and ¹³C NMR spectra were obtained on Varian Unity PlusNMR spectrophotometers at 300 or 400 MHz, and 75 or 100 MHzrespectively. ¹⁹F NMR were recorded at 282 MHz. Mass spectra wereobtained on Micromass Platform, or ZMD mass spectrometers from MicromassLtd. Altrincham, UK, using either Atmospheric Chemical Ionization (APCI)or Electrospray Ionization (ESI). Analytical thin layer chromatographywas used to verify the purity of some intermediates which could not beisolated or which were too unstable for full characterization, and tofollow the progress of reactions. Unless otherwise stated, this was doneusing silica gel (Merck Silica Gel 60 F254). Unless otherwise stated,column chromatography for the purification of some compounds, used MerckSilica gel 60 (230-400 mesh), and the stated solvent system underpressure. All compounds were characterized as their free-base formunless otherwise stated. On occasion the corresponding hydrochloridesalts were formed to generate solids where noted.

EXAMPLE 1N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-pyridinyl)pyrazolo[1,5-a]pyridin-7-amine

[0462]

[0463] a) 2-(6-Chloro-2-pyridinyl)-1-(4-pyridinyl)ethanone oxime.

[0464] To a cold (0° C.) solution of 6-chloro-2-picoline (14.5 mL, 132.3mmol) and ethyl isonicotinate (20.0 g, 132.3 mmol) in tetrahydrofuran(300 mL) was added lithium bis(trimethylsilyl)amide (280 mL, 1.0 M intetrahydrofuran, 278 mmol) dropwise via a pressure equalizing funnelover 1 hour. Upon complete addition, the cold bath was removed and theresulting solution was heated at 45° C. for 15 hours. The mixture wascooled to room temperature, methanol was added, and the solution wasconcentrated to give 2-(6-chloro-2-pyridinyl)-1-(4-pyridinyl)ethanone asa syrup, that was used without further purification. This syrup (11.7 g,50 mmol) was dissolved in methanol (200 mL). To this solution was addedhydroxylamine hydrochloride (17.5 g, 250 mmol) followed by the additionof a sodium hydroxide solution (10 g, 250 mmol in 30 mL of water). Theresulting suspension was heated at reflux for 2 hours and then allowedto cool to room temperature. The mixture was concentrated and water wasadded to the resulting slurry. A white precipitate formed, which wascollected by filtration, washed with water and dried to give2-(6-chloro-2-pyridinyl)-1-(4-pyridinyl)ethanone oxime (10.5 g, 85%) asa white solid. ¹H NMR (CDCl₃): δ 9.6 (broad s, 1H), 8.65 (d, 2H), 7.70(d, 2H), 7.58 (t, 1H), 7.22 (m, 2H), 4.40 (s, 2H); MS m/z 248 (M+1).

[0465] b) 7-Chloro-2-(4-pyridinyl)pyrazolo[1,5-a]pyridine.

[0466] To a solution of 2-(6-chloro-2-pyridinyl)-1-(4-pyridinyl)ethanoneoxime (6.0 g, 24 mmol) in 1,2-dimethoxyethane (40 mL) at 0° C. was addedtrifluoroacetic anhydride (3.4 mL, 24 mmol), keeping the temperaturebelow 10° C. during the addition. After the addition was complete, thereaction was warmed to room temperature. The solution was then cooled to4° C. and a solution of triethylamine (6.7 mL, 48 mmol) in1,2-dimethoxyethane (15 mL) was added over a period of 0.5 hours. Themixture was allowed to warm to room temperature and was stirred for 1.5hours. To this mixture was added iron(II) chloride (50 mg) and thereaction was heated at 75° C. for 15 hours. The reaction mixture waspoured into water (300 mL). The resulting suspension was extracted withethyl acetate. The ethyl acetate phase was dried (magnesium sulfate),filtered and concentrated to a solid residue. This residue was purifiedby silica gel chromatography (1:1 ethyl acetate-hexane) to give7-chloro-2-(4-pyridinyl)pyrazolo[1,5-a]pyridine (2.8 g, 50%) as a tansolid. ¹H NMR (d₆-DMSO): δ 8.62 (m, 2H), 7.93 (m, 2H), 7.76 (dd, 1H),7.42 (m, 2H), 7.24 (m, 1H); MS m/z 230 (M+1).

[0467] c)1-[7-Chloro-2-(4-pyridinyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone.

[0468] To a solution of 7-chloro-2-(4-pyridinyl)pyrazolo[1,5-a]pyridine(2.0 g, 8.7 mmol) in acetonitrile (50 mL) at room temperature was addedacetic anhydride (2.0 mL, 21 mmol). Boron trifluoride diethyletherate(5.3 mL, 42 mmol) was added dropwise and the resulting solution washeated at 80° C. for 12 hours. The reaction mixture was cooled to roomtemperature and quenched by the dropwise addition of saturated sodiumbicarbonate. The reaction mixture was extracted with ethyl acetate, andthe organic phase phase washed with brine, dried (magnesium sulfate),filtered and concentrated. The residue was purified by silica gelchromatography (5:95 methanol-dichloromethane) to give1-[7-chloro-2-(4-pyridinyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone (1.53 g,65%) as a red foam. ¹H NMR (CDCl₃): δ 8.82 (m, 2H), 8.45 (d, 1H), 7.62(m, 2H), 7.54 (t, 1H), 7.25 (d, 1H), 2.26 (s, 3H); MS m/z 272 (M+1).

[0469] d)1-[7-(Cyclopentylamino)-2-(4-pyridinyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone.

[0470] To a solution of1-[7-chloro-2-(4-pyridinyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone (0.68 g,2.5 mmol) in toluene (10 mL) was added successivelyrac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (100 mg, 0.15 mmol),cesium carbonate (1.2 g, 3.8 mmol), cyclopentylamine (1.5 mL, 12.5mmol), and palladium (II) acetate (25 mg, 0.1 mmol). The resultingmixture was stirred at 90° C. for 24 hours, at which time the reactionwas judged complete by thin layer chromatography. The solution wascooled to room temperature and ethyl acetate and water were added to thereaction mixture. The phases were separated, and the aqueous phase againextracted with ethyl acetate. The combined organic phases were dried(magnesium sulfate), filtered and concentrated. The resulting residuewas purified by flash chromatography (1:1 hexanes-ethyl acetate) to give1-[7-(cyclopentylamino)-2-(4-pyridinyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone(0.64 g, 80%) as a yellow foam. ¹H NMR (CDCl₃): δ 8.80 (d, 2H), 7.65 (d,1H), 7.60 (d, 2H), 7.50 (t, 1H), 6.20 (d, 1H), 6.06 (d, 1H), 4.0 (m,1H), 2.26 (s, 3H), 1.6-2.2 (m, 8H); MS m/z 321 (M+1).

[0471] e) N-Cyclopentylguanidine hydrochloride.

[0472] This compound was prepared by modification of a procedure fromBannard, R. A. B.; Casselman, A. A.; Cockburn, W. F.; and Brown, G. M.Can. J. Chem. 1958, 36, 1541-1549). To a solution of2-methyl-2-thiopseudourea sulfate (13.9 g, 50.0 mmol) in water (40 mL)was added cyclopentylamine (14.8 mL, 150 mmol). The resultant mixturewas heated to 55° C. for 20 minutes and then to reflux for 2.5 hours.The mixture was cooled to room temperature and concentrated in vacuo andazeotroped with methanol. Water was added (˜100 mL) and Amberlite IRA400 (Cl⁻) resin was added. The mixture was stirred for 1 hour and thenthe resin was removed by filtration. The solution was concentrated invacuo and azeotroped with methanol. The residue was recrystallized frommethanol-acetone to yield N-cyclopentylguanidine hydrochloride (7.0 g,86%) as a fine white solid. ¹H NMR (D₂O): δ 3.62 (m, 1H), 1.75 (m, 2H),1.52-1.32 (m, 6H); ¹³C NMR (D₂O): δ 156.23, 53.11, 32.15, 23.13; MS m/z128 (M+1).

[0473] f)N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-pyridinyl)pyrazolo[1,5-a]pyridin-7-amine.

[0474] A solution of1-[7-(cyclopentylamino)-2-(4-pyridinyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone(0.3 g, 0.94 mmol) in N,N-dimethylformamide dimethyl acetal (10 mL) washeated at reflux for 3 days. The mixture was allowed to cool to roomtemperature. Water was added and the resulting mixture was extractedwith ethyl acetate. The ethyl acetate phase was dried (magnesiumsulfate), filtered and concentrated. The resulting residue was purifiedby flash chromatography (7:3 ethyl acetate-acetone) to give1-[7-(cyclopentylamino)-2-(4-pyridinyl)pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one(0.23 g, 65%) as a colored syrup which was used in the next step withoutfurther purification. To a solution of1-[7-(cyclopentylamino)-2-(4-pyridinyl)pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one(0.10 g, 0.27 mmol) in tetrahydrofuran (10 mL) was added cyclopentylguanidine hydrochloride (0.06 g, 0.38 mmol) followed by potassiumtert-butoxide (0.085 g, 0.76 mmol). The resulting mixture was heated atreflux for 12 hours. Upon cooling to room temperature, water was added.The mixture was extracted with ethyl acetate. The ethyl acetate phasewas washed with brine, dried (magnesium sulfate), filtered andconcentrated in vacuo. The resulting residue was purified by flashchromatography (1:9 methanol-dichloromethane) to give the title compound(89 mg, 75%) as a white solid. ¹H NMR (CDCl₃): δ 8.64 (d, 2H), 8.04 (d,1H), 7.58 (m, 3H), 7.28 (t, 1H), 6.32 (d, 1H), 6.02 (d, 1H), 5.95 (d,1H), 5.03 (d, 1H), 4.22 (m, 1H), 3.97 (m, 1H), 1.2-2.2 (m, 16H); MS m/z440 (M+1).

EXAMPLE 2N-Cyclopentyl-3-[2-(methylamino)-4-pyrimidinyl]-2-(4-pyridinyl)pyrazolo[1,5-a]pyridin-7-amine

[0475]

[0476] To a solution of1-[7-(cyclopentylamino)-2-(4-pyridinyl)pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one(From example 1, 0.13 g, 0.35 mmol) in tetrahydrofuran (10 mL) was addedcyclopentyl guanidine hydrochloride (0.06 g, 0.38 mmol) followed bypotassium tert-butoxide (0.085 g, 0.76 mmol). The resulting mixture washeated at reflux for 12 hours. Upon cooling to room temperature, waterwas added. The mixture was extracted with ethyl acetate. The ethylacetate phase was washed with brine, dried (magnesium sulfate), filteredand concentrated in vacuo. The resulting residue was purified by flashchromatography (1:20 methanol-ethyl acetate) to give the title compound(100 mg, 750/0) as a yellow solid. ¹H NMR (CDCl₃): δ 8.72 (d, 2H), 8.13(d, 1H), 7.65 (m, 3H), 7.35 (t, 1H), 6.43 (d, 1H), 6.10 (d, 1H), 6.05(d, 1H), 5.10 (m, 1H), 4.05 (m, 1H), 3.05 (d, 3H), 1.2-2.2 (m, 8H); MSm/z 386 (M+1).

EXAMPLE 3N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(3-pyridinyl)pyrazolo[1,5-a]pyridin-7-amine

[0477]

[0478] a) 2-(6-Chloro-2-pyridinyl)-1-(3-pyridinyl)ethanone oxime.

[0479] In a similar manner as described in Example 1 from6-chloro-2-picoline (9.3 g, 73 mmol) and methyl nicotinate (10.0 g, 73mmol), 2-(6-chloro-2-pyridinyl)-1-(3-pyridinyl)ethanone was obtained asa syrup. This syrup (10 g, 70 mmol) was treated with hydroxylaminehydrochloride (24.3 g, 350 mmol) followed by the addition of a sodiumhydroxide solution (14 g, 350 mmol in 30 mL of water) as described inexample 1 to give 2-(6-chloro-2-pyridinyl)-1-(3-pyridinyl)ethanone oxime(14.4 g, 80%) as a white solid. ¹H NMR (CDCl₃): δ 8.84 (d, 1H), 8.40(dd, 1H), 8.00 (m, 1H), 7.50 (t, 1H), 7.2-7.4 (m, 3H), 4.26 (s, 2H); MSm/z 248 (M+1).

[0480] b) 7-Chloro-2-(3-pyridinyl)pyrazolo[1,5-a]pyridine.

[0481] In a similar manner as described in Example 1 from2-(6-chloro-2-pyridinyl)-1-(3-pyridinyl)ethanone oxime (9.6 g, 39 mmol)was obtained 7-chloro-2-(3-pyridinyl)pyrazolo[1,5-a]pyridine (2.8 g,50%) as a tan solid. ¹H NMR (CDCl₃): δ 9.20 (d, 1H), 8.64 (dd, 1H), 8.44(dt, 1H), 7.56 (d, 1H), 7.48 (dd, 1H), 7.14 (dd, 1H), 7.0 (s, 1H), 6.96(d, 1H); MS m/z 230 (M+1).

[0482] c)1-[7-Chloro-2-(3-pyridinyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone.

[0483] In a similar manner as described in Example 1 from7-chloro-2-(3-pyridinyl)pyrazolo[1,5-a]pyridine (1.5 g, 6.5 mmol) wasobtained 1-[7-chloro-2-(3-pyridinyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone(1.4 g, 60%) as a foam. ¹H NMR (CDCl₃): δ 8.90 (broad s, 1H), 8.77 (d,1H), 8.40 (d, 1H), 8.00 (dt, 1H), 7.50 (m, 2H), 7.20 (d, 1H), 2.21 (s,3H); MS m/z 272 (M+1).

[0484] d)1-[7-(Cyclopentylamino)-2-(3-pyridinyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone.

[0485] In a similar manner as described in Example 1 from1-[7-chloro-2-(3-pyridinyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone (0.95 g,3.5 mmol) was obtained1-[7-(cyclopentylamino)-2-(3-pyridinyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone(0.78 g, 70%) as a yellow foam. ¹H NMR (CDCl₃): δ 8.88 (s, 1H), 8.73 (m,1H), 8.01 (d, 1H), 7.61 (d, 1H), 7.44 (m, 2H), 6.17 (d, 1H), 6.05 (d,1H), 4.00 (m, 1H), 2.23 (s, 3H), 1.6-2.2 (m, 8H); MS m/z 321 (M+1).

[0486] e) N-Cyclopentyl-3-[2-(cyclopentylmethyl)-4-pyrimidinyl]-2-(3-pyridinyl)pyrazolo[1,5-a]pyridin-7-amine.

[0487] In a similar manner as described in Example 1 from1-[7-(cyclopentylamino)-2-(4-pyridinyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone(0.56 g, 1.8 mmol) was obtainedN-cyclopentyl-3-[2-(cyclopentylmethyl)-4-pyrimidinyl]-2-(3-pyridinyl)pyrazolo[1,5-a]pyridin-7-amine(192 mg, 20% over 2 steps) as a white solid. ¹H NMR (CDCl₃): δ 8.90 (s,1H), 8.63 (m, 1H), 8.05 (d, 1H), 7.95 (m, 1H), 7.65 (d, 1H), 7.3 (m,2H), 6.30 (d, 1H), 6.0 (m, 1H), 5.35 (d, 1H), 4.25 (m, 2H), 3.98 (m,1H), 1.5-2.2 (m, 16H); MS m/z 440 (M+1).

EXAMPLE 4N-Cyclopentyl-N-(4-{2-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-3-yl}-2-pyrimidinyl)amine

[0488]

[0489] a) 4-Ethynyl-2-(methylsulfanyl)pyrimidine.

[0490] 4-Iodo-2-(methylsulfanyl)pyrimidine (2.0 g, 8.1 mmol) wasdissolved in anhydrous tetrahydrofuran (50 mL). To this solution wasadded triethylamine (1.4 mL, 10.1 mmol), copper (I) iodide (80 mg, 0.4mmol) and dichlorobis(triphenylphosphine) palladium (II) (140 mg, 0.24mmol). (Trimethylsilyl)acetylene (1.4 mL, 10.1 mmol) was added dropwiseto the resulting solution. After the addition of(trimethylsilyl)acetylene was complete the reaction was stirred at roomtemperature for 2 hours. Hexane was added to the reaction mixture andthe mixture was filtered to remove precipitates. The solution wasconcentrated to give a syrup, that was purified by silica gelchromatography (1:1 ethyl acetate:hexane) to give 1.76 g (99%) of2-(methylsulfanyl)-4-[(trimethylsilyl)ethynyl]pyrimidine.2-(Methylsulfanyl)-4-[(trimethylsilyl)ethynyl]pyrimidine (1.76 g, 8.0mmol) was dissolved in methanol (60 mL). To this solution was addedpotassium fluoride (467 mg, 8.0 mmol) and the resulting mixture stirredat room temperature for 5 minutes. The solution was concentrated andethyl acetate and water were added. The phases were separated and theaqueous phase extracted with additional ethyl acetate. The organics werecombined, dried over magnesium sulfate, filtered and concentrated togive 1.0 g (83%) of 4-ethynyl-2-(methylsulfanyl)pyrimidine as a whitesolid. ¹H NMR (CDCl₃): δ 8.51 (d, 1H), 7.06 (d, 1H), 3.34 (s, 1H), 2.56(s, 3H); MS m/z 151 (M+1).

[0491] b)2-(Methylsulfanyl)-4-{[2-(methylsulfanyl)-4-pyrimidinyl]ethynyl}pyrimidine.

[0492] 4-Iodo-2-(methylsulfanyl)pyrimidine (1.76 g, 7.1 mmol) wasdissolved in anhydrous tetrahydrofuran (50 mL). To this solution wasadded triethylamine (1.2 mL, 8.5 mmol), copper (I) iodide (70 mg, 0.4mmol) and dichlorobis(triphenylphosphine)palladium (II) (150 mg, 0.21mmol). A solution of 4-ethynyl-2-(methylsulfanyl)pyrimidine (1.0 g, 7.1mmol) in tetrahydrofuran was added dropwise. The reaction mixture wasstirred at room temperature overnight Ethyl acetate and water were addedto the reaction mixture. The phases were separated and the aqueous phaseextracted with additional ethyl acetate. The organics were combined,dried over magnesium sulfate, filtered and concentrated. Purification bysilica gel chromatography (1:1 ethyl acetate:hexane) gave 1.35 g (69%)of2-(methylsulfanyl)-4-{[2-(methylsulfanyl)-4-pyrimidinyl]ethynyl}pyrimidineas a white solid. ¹H NMR (CDCl₃): δ 8.57 (d, 2H), 7.19 (d, 2H), 2.59 (s,6H); MS m/z 275 (M+1).

[0493] c)2,3-Bis[2-(methylsulfanyl)-4-pyrimidinyl]pyrazolo[1,5-a]pyridine.

[0494]2-(Methylsulfanyl)-4-{[2-(methylsulfanyl)-4-pyrimidinyl]ethynyl}pyrimidine(0.1 g, 0.37 mmol) was dissolved in acetonitrile (5 mL). To thissolution was added 1-aminopyridinium iodide (81 mg, 0.37 mmol) and1,8-diazobicyclo[5.4.0]undec-7-ene (0.056 mL, 0.37 mmol) and theresulting mixture was stirred at room temperature overnight. Theresulting reddish suspension was concentrated in vacuo. Ethyl acetateand water were added to this residue. The phases were separated and theaqueous phase extracted with additional ethyl acetate. The organics werecombined, dried over magnesium sulfate, filtered and concentrated.Purification by silica gel chromatography (1:1 ethyl acetate:hexane)gave 95 mg (71%) of2,3-bis[2-(methylsulfanyl)-4-pyrimidinyl]pyrazolo[1,5-a]pyridine as asolid. ¹H NMR (CDCl₃): δ 8.64 (d, 1H), 8.53 (d, 1H), 8.41 (d, 1H), 8.31(d, 1H), 7.56 (d, 1H), 7.37 (t, 1H), 7.13 (d, 1H), 7.00 (t, 1H), 2.59(s, 3H), 2.37 (s, 3H); MS m/z 367 (M+1).

[0495] d)N-Cyclopentyl-N-(4-{2-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-3-yl}-2-pyrimidinyl)amine.

[0496] 2,3-Bis[2-(methylsulfanyl)-4-pyrimidinyl]pyrazolo[1,5-a]pyridine(0.35 g, 0.96 mmol) was dissolved in dichloromethane (20 mL) and theresulting solution cooled to 0° C. in an ice bath. To this solution wasadded dropwise 3-chloroperoxybenzoic acid (824 mg, 57-86%) indichloromethane. This reaction mixture was stirred at 0° C. for 10minutes. Additional dichloromethane was added and the reaction mixturewas extracted with saturated aqueous potassium carbonate. The organicphase was dried over magnesium sulfate, filtered and concentrated togive a foam. This foam was dissolved in cyclopentylamine and heated to60° C. for 2 hours. The resulting mixture was concentrated to a solidthat was recrystallized from acetonitrile to give 210 mg (50%) ofN-cyclopentyl-N-(4-{2-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-3-yl}-2-pyrimidinyl)amineas a solid. ¹H NMR (CDCl₃): δ 8.52 (d, 1H), 8.34 (d, 1H), 8.27 (d, 1H),8.14 (d, 1H), 7.29 (t, 1H), 6.90 (m, 2H), 6.62 (d, 1H), 5.23 (m, 2H),4.30 (m, 1H), 4.20 (broad s, 1H), 1.8-2.1 (m, 4H), 1.4-1.8 (m, 12H); MSm/z 441 (M+1).

EXAMPLE 5N-(4-{7-Chloro-2-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-3-yl}-2-pyrimidinyl)-N-cyclopentylamine

[0497]

[0498]N-Cyclopentyl-N-(4-{2-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-3-yl}-2-pyrimidinyl)amine(140 mg, 0.32 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL).The resulting solution was cooled to −78° C., then n-butyllithium (0.99mL, 1.6 mmol, 1.6 M in hexane) was added dropwise. The resulting darksolution was stirred at −78° C. for 20 minutes, then carbontetrachloride (2 mL) was added. The reaction was stirred for additional20 minutes and then quenched by the addition of water and allowed towarm to room temperature. The phases were separated and the aqueousphase extracted with ethyl acetate. The organics were combined, driedover magnesium sulfate, filtered and concentrated. Purification bysilica gel chromatography (1:1 ethyl acetate:hexane) gave 80 mg (53%) ofN-(4-{7-chloro-2-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-3-yl}-2-pyrimidinyl)-N-cyclopentylamineas a foam. ¹H NMR (CDCl₃): δ 8.37 (d, 1H), 8.27 (d, 1H), 8.16 (d, 1H),7.26 (t, 1H), 7.06 (d, 1H), 7.04 (m, 1H), 6.62 (d, 1H), 5.21 (d, 1H),5.15 (d, 1H), 4.32 (m, 1H), 4.10 (m, 1H), 1.4-2.1 (m, 16H); MS m/z 475(M+1).

EXAMPLE 6N-Cyclopentyl-2,3-bis[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine

[0499]

[0500] a)N-(4-{7-Chloro-2-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-3-yl}-2-pyrimidinyl)-N-cyclopentylamine(60 mg, 0.13 mmol) was dissolved in cyclopentylamine (4 mL). To thissolution was added successivelyrac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (31 mg, 0.05 mmol),cesium carbonate (61 mg, 0.18 mmol) and palladium (II) acetate (6 mg,0.03 mmol). The resulting mixture was stirred at 90° C. for 24 hours, atwhich time the reaction was judged complete by thin layerchromatography. The solution was cooled to room temperature and ethylacetate and water were added to the reaction mixture. The phases wereseparated, and the aqueous phase again extracted with ethyl acetate. Thecombined organic phases were dried (magnesium sulfate), filtered andconcentrated. The resulting residue was purified by flash chromatography(1:1 hexanes:ethyl acetate) to give 20 mg (30%) ofN-cyclopentyl-2,3-bis[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amineas a foam. ¹H NMR (CDCl₃): δ 8.38 (d, 1H), 8.02 (broad s, 1H), 7.63 (d,1H), 7.33 (t, 1H), 6.93 (s, 1H), 6.59 (d, 1H), 6.07 (d, 1H), 6.03 (m,1H), 5.21 (m, 1H), 4.32 (m, 1H), 4.23 (m, 1H), 4.00 (m, 1H), 1.4-2.2 (m,24H); MS m/z 524 (M+1).

EXAMPLE 7N-(2-Methoxyethyl)-2,3-bis{2-[(2-methoxyethyl)amino]pyrimidin-4-yl}pyrazolo[1,5-a]pyridin-7-amine

[0501]

[0502] To a −78° C. solution of2,3-bis[2-(methylsulfanyl)pyrimidin-4-yl]pyrazolo[1,5-a]pyridine (0.72g, 2.0 mmol) in tetrahydrofuran (50 mL) was added a 2 M solution oflithium diisopropylamide in heptane/tetrahydrofuran/ethylbenzene (2.9mL, 5.9mmol) dropwise. The reaction mixture was stirred for 15 minutes,then carbon tetrachloride (5 mL) was added. The reaction mixture wasstirred for 1 hour and quenched with brine and extracted with ethylacetate (3×25 mL). The organic phase was washed with brine (3×25 mL),dried over magnesium sulfate, and concentrated under reduced pressure.The residue was purified by silica gel chromatography (1:9acetone:dichloromethane) to give 260 mg (32%) of7-chloro-2,3-bis[2-(methylsulfanyl)pyrimidin-4-yl]pyrazolo[1,5-a]pyridine.7-Chloro-2,3-bis[2-(methylsulfanyl)pyrimidin-4-yl]pyrazolo[1,5-a]pyridine(0.098 g, 0.24 mmol) was dissolved in dichlormethane (3 mL) and cooledto 0° C. To the solution was added 3-chloroperoxybenzoic acid (0.13 g,0.73 mmol). The reaction mixture was allowed to warm to room temperatureand stirred overnight. The mixture was diluted with dichloromethane,washed with saturated aqueous sodium bicarbonate, and concentrated underreduced pressure. To7-chloro-2,3-bis[2-(methylsulfinyl)pyrimidin-4-yl]pyrazolo[1,5-a]pyridine(0.027 g, 0.062 mmol) was added 2-methoxyethylamine (2 mL) and thereaction was heated to 100° C. in a sealed tube overnight. The reactionmixture was cooled to room temperature and concentrated by evaporationunder reduced pressure. The residue was purified by silica gelchromatography eluting with 1:1 acetone:dichloromethane to give 15 mg(49%) ofN-(2-methoxyethyl)-2,3-bis{2-[(2-methoxyethyl)amino]pyrimidin-4-yl}pyrazolo[1,5-a]pyridin-7-amine.¹H NMR (CDCl₃): δ 8.41 (d, 1H), 8.16 (d, 1H), 7.69 (d, 1H), 7.36 (d,1H), 7.05 (m, 1H), 6.65 (d, 1H), 6.33 (t, 1H), 6.09 (d, 1H), 5.57 (m,1H), 5.42 (t, 1H), 3.37-3.80 (m, 21H); MS m/z 494 (M+1).

EXAMPLE 8N-Butyl-2,3-bis[2-(butylamino)pyrimidin-4-yl]pyrazolo[1,5-a]pyridin-7-amine

[0503]

[0504]N-Butyl-2,3-bis[2-(butylamino)pyrimidin-4-yl]pyrazolo[1,5-a]pyridin-7-aminewas prepared by treating7-chloro-2,3-bis[2-(methylsulfinyl)pyrimidin-4-yl]pyrazolo[1,5-a]pyridinewith n-butylamine as described in Example 7. ¹H NMR, (400 MHz, CDCl₃): δ8.35 (d, 1H), 8.09 (d, 1H), 7.62 (d, 1H), 7.30 (t, 1H), 6.93 (m, 1H),6.57 (d, 1H), 6.40 (d, 1H), 6.20 (d, 1H), 5.17 (m, 1H), 5.08 (m, 1H),3.343.46 (m, 6H), 1.75 (m, 2H), 1.35-1.66 (m, 10H), 0.90-1.00 (m, 9H);MS m/z 488 (M+1).

EXAMPLE 9N-Cyclopropyl-2,3-bis[2-(cyclopropylamino)pyrimidin-4-yl]pyrazolo[1,5-a]pyridin-7-amine

[0505]

[0506]N-Cyclopropyl-2,3-bis[2-(cyclopropylamino)pyrimidin-4-yl]pyrazolo[1,5-a]pyridin-7-aminewas prepared by treating7-chloro-2,3-bis[2-(methylsulfinyl)pyrimidin-4-yl]pyrazolo[1,5-a]pyridinewith cyclopropylamine as described in Example 7. ¹H NMR, (CDCl₃): δ 8.47(d, 1H), 8.19 (d, 1H), 7.86 (d, 1H), 7.37 (t, 1H), 7.04 (d, 1H), 6.71(d, 1H), 6.44 (d, 1H), 6.36 (s, 1H), 5.53 (s, 1H), 5.39 (s, 1H),2.62-290 (m, 3H), 0.77-0.96 (m, 8H), 0.56-0.70 (m, 4H); MS m/z 440(M+1).

EXAMPLE 107-Morpholin-4-yl-2,3-bis(2-morpholin-4-ylpyrimidin-4-yl)pyrazolo[1,5-a]pyridine

[0507]

[0508]7-Morpholin-4-yl-2,3-bis(2-morpholin-4-ylpyrimidin-4-yl)pyrazolo[1,5-a]pyridinewas prepared by treating7-chloro-2,3-bis[2-(methylsulfinyl)pyrimidin-4-yl]pyrazolo[1,5-a]pyridinewith morpholine as described in Example 7. ¹H NMR, (400 MHz, CDCl₃): δ8.43 (d, 1H), 8.21 (d, 1H), 7.83 (d, 1H), 7.28 (dd, 1H), 7.19 (d, 1H),6.71 (d, 1H), 6.34 (d, 1H), 4.01 (t, 4H), 3.80 (m, 8H), 3.67 (m, 8H),3.49 (m, 4H); MS m/z 530 (M+1).

EXAMPLE 11N-Isobutyl-2,3-bis[2-(isobutylamino)pyrimidin-4-yl]pyrazolo[1,5-a]pyridin-7-amine

[0509]

[0510]N-Isobutyl-2,3-bis[2-(isobutylamino)pyrimidin-4-yl]pyrazolo[1,5-a]pyridin-7-aminepyridine was prepared by treating7-chloro-2,3-bis[2-(methylsulfinyl)pyrimidin-4-yl]pyrazolo[1,5-a]pyridinewith isobutylamine as described in Example 7. ¹H NMR, (400 MHz, CDCl₃):δ 8.35 (d, 1H), 8.09 (d, 1H), 7.59 (d, 1H), 7.30 (d, 1H), 6.94 (bs, 1H),6.57 (m, 1H), 6.16 (t, 1H), 6.00 (d, 1H), 5.26 (bs, 1H), 5.17 (bs, 1H),3.25 (t, 3H), 3.18 (t, 3H), 2.00-2.15 (m, 1H), 1.85-1.95 (m, 2H),0.90-1.10 (m, 18H); MS m/z 488 (M+1).

EXAMPLE 12N-Benzyl-2,3-bis[2-(benzylamino)pyrimidin-4-yl]pyrazolo[1,5-a]pyridin-7-amine

[0511]

[0512]N-Benzyl-2,3-bis[2-(benzylamino)pyrimidin-4-yl]pyrazolo[1,5-a]pyridin-7-aminewas prepared by treating7-chloro-2,3-bis[2-(methylsulfinyl)pyrimidin-4-yl]pyrazolo[1,5-a]pyridinewith benzylamine as described in Example 7. ¹H NMR, (400 MHz, CDCl₃): δ8.37 (d, 1H), 8.02 (d, 1H), 7.16-7.40 (m, 16H), 7.12 (t, 1H), 7.02 (bs,1H), 6.63 (d, 1H), 6.48 (t, 1H), 5.96 (d, 1H), 5.58 (bs, 1H), 5.46 (1H),4.65 (d, 2H), 4.38-4.62 (m, 4H); MS m/z 590 (M+1).

EXAMPLE 13N-Isopropyl-2,3-bis[2-(isopropylamino)pyrimidin-4-yl]pyrazolo[1,5-a]pyridin-7-amine

[0513]

[0514]N-Isopropyl-2,3-bis[2-(isopropylamino)pyrimidin-4-yl]pyrazolo[1,5-a]pyridin-7-aminewas prepared by treating7-chloro-2,3-bis[2-(methylsulfinyl)pyrimidin-4-yl]pyrazolo[1,5-a]pyridinewith isopropylamine as described in Example 7. ¹H NMR, (CDCl₃): δ 8.39(d, 1H), 8.14 (d, 1H), 7.52 (m, 1H), 7.36 (d, 1H), 6.96 (m, 1H), 6.60(d, 1H), 6.06 (d, 1H), 5.99 (d, 1H), 5.08 (m, 1H), 4.99 (m, 1H),4.05-4.25 (m, 2H), 3.80-3.99 (m, 1H), 1.42 (d, 6H), 1.30 (d, 6H), 1.24(m, 6H); MS m/z 446 (M+1).

EXAMPLE 142-(2-Fluoro-4-pyridinyl)-3-[2-(methylsulfanyl)-4-pyrimidinyl]pyrazolo-[1,5-a]pyridine

[0515]

[0516] a)4-[(2-Fluoro-4-pyridinyl)ethynyl]-2-(methylsulfanyl)pyrimidine.

[0517] 4-Iodo-2-fluoropyridine (1.09 g, 4.9 mmol) was dissolved inanhydrous tetrahydrofuran (20 mL). To this solution was addedtriethylamine (0.9 mL, 6.5 mmol), copper (I) iodide (80 mg, 0.4 mmol)and dichlorobis(triphenylphosphine) palladium (II) (60 mg, 0.32 mmol).4-Ethynyl-2-(methylsulfanyl)pyrimidine (example 4,0.75 g, 4.9 mmol) intetrahydrofuran was added dropwise to the resulting solution. After theaddition was complete the reaction was stirred at room temperatureovernight. The mixture was concentrated to give a syrup, that waspurified by silica gel chromatography (1:1 ethyl acetate:hexane) to giveafter removal of solvents 0.84 g (70%) of4-[(2-fluoro-4-pyridinyl)ethynyl]-2-(methylsulfanyl)pyrimidine as awhite solid. ¹H NMR (CDCl₃): δ 8.61 (d, 1H), 8.32 (d, 1H), 7.39 (d, 1H),7.17 (m, 2H), 2.64 (s, 3H); ¹⁹F NMR (CDCl₃): δ −66.82; MS m/z 246 (M+1).

[0518] b)2-(2-Fluoro-4-pyridinyl)-3-[2-(methylsulfanyl)-4-pyrimidinyl]pyrazolo[1,5-a]pyridine.4-[(2-Fluoro-4-pyridinyl)ethynyl]-2-(methylsulfanyl)pyrimidine (740 mg,3.0 mmol) was dissolved in acetonitrile (10 mL). To this solution wasadded 1-aminopyridinium iodide (670 mg, 3.0 mmol) and1,8-diazobicyclo[5.4.0]undec-7-ene (0.460 mL, 3.0 mmol) at 0° C. and theresulting mixture was allowed to warm to room temperature and stirred atroom temperature for 2 days. The resulting reddish suspension wasconcentrated in vacuo. Ethyl acetate and water were added to thisresidue. The phases were separated and the aqueous phase extracted withadditional ethyl acetate. The organics were combined, dried overmagnesium sulfate, filtered and concentrated. Purification by silica gelchromatography (1:1 ethyl acetate:hexane) gave 550 mg (55%) of2-(2-fluoro-4-pyridinyl)-3-[2-(methylsulfanyl)-4-pyrimidinyl]pyrazolo[1,5-a]pyridineas a solid. ¹H NMR (CDCl₃): δ 8.62 (d, 1H), 8.41 (d, 1H), 8.39 (d, 1H),8.35 (d, 1H), 7.47 (m, 2H), 7.25 (m, 1H), 7.06 (dt, 1H), 6.83 (d, 1H),2.53 (s, 3H); ¹⁹F NMR δ (CDCl₃): −67.12; ¹³C NMR (CDCl₃): δ 173.16,164.23 (d, J_(CF) 239.7 Hz), 159.67, 156.97, 150.17 (d, J_(CF) 3.1 Hz),148.29 (d, J_(CF) 15.3 Hz), 146.73, (d, J_(CF) 8.3 Hz), 141.07, 129.08,127.10, 122.05 (d, J_(CF) 3.8 Hz), 119.80, 114.82,114.56,110.07 (d,J_(CF) 38.1 Hz), 107.96; MS 338 m/z (M+1).

EXAMPLE 154-[2-(2-Fluoro-4-pyridinyl)pyrazolo[1,5-a]pyridin-3-yl]-N-isopropyl-2-pyrimidinamine

[0519]

[0520]2-(2-Fluoro-4-pyridinyl)-3-[2-(methylsulfanyl)-4-pyrimidinyl]pyrazolo[1,5-a]pyridine(0.18 g, 0.53 mmol) was dissolved in dichloromethane (10 mL) and theresulting solution cooled to 0° C. in an ice bath. To this solution wasadded dropwise 3-chloroperoxybenzoic acid (230 mg, 57-86%) indichloromethane. This reaction mixture was stirred at 0° C. for 10minutes. Additional dichloromethane was added and the reaction mixturewas extracted with saturated aqueous potassium carbonate. The organicphase was dried over magnesium sulfate, filtered and concentrated togive a foam. This foam was dissolved in isopropylamine and heated to 50°C. for 2 hours. The resulting mixture was concentrated to a solid thatwas purified by by silica gel chromatography (1:1 ethyl acetate:hexane)give 90 mg (48%) of the title compound as a solid. ¹H NMR (CDCl₃): δ8.56 (d, 1H), 8.31 (m, 2H), 8.19 (d, 1H), 7.52 (m, 1H), 7.40 (t, 1H),7.33 (broad s, 1H), 7.02 (t, 1H), 6.45 (d, 1H), 5.20 (m, 1H), 4.20 (m,1H), 1.31 (d, 5H); ¹⁹F NMR (CDCl₃): δ −67.68; MS m/z 349 (M+1).

EXAMPLE 16N-Isopropyl-4-{2-[2-(isopropylamino)-4-pyridinyl]pyrazolo[1,5-a]pyridin-3-yl}-2-pyrimidinamine

[0521]

[0522]4-[2-(2-Fluoro-4-pyridinyl)pyrazolo[1,5-a]pyridin-3-yl]-N-isopropyl-2-pyrimidinamine(80 mg, 0.23 mmol) was dissolved in isopropylamine (10 mL) in a pressurevessel and the resulting solution heated at 120° C. for 4 days. Theresulting mixture was concentrated to a solid that was purified by bysilica gel chromatography (1:1 ethyl acetate:hexane) to give 50 mg (56%)of the title compound as a solid. ¹H NMR (CDCl₃): δ 8.53 (d, 1H), 8.43(d, 1H), 8.1.5 (two d, 2H), 7.35 (t, 1H), 6.96 (t, 1H), 6.82 (d, 1H),6.65 (s, 1H), 6.50 (d, 1H), 5.08 (d, 1H), 4.60 (d, 1H), 4.25 (m, 1H),3.94 (m, 1H), 1.33 (d, 6H), 1.25 (d, 6H); MS m/z 388 (M+1).

EXAMPLE 173-[2-(Cyclopropylamino)-4-pyrimidinyl]-N-isopropyl-2-[2-(isopropylamino)-4-pyridinyl]pyrazolo[1,5-a]pyridin-7-amine

[0523]

[0524] a)2-(2-Fluoro-4-pyridinyl)-3-[2-(methylsulfinyl)-4-pyrimidinyl]pyrazolo[1,5-a]pyridine.

[0525] To a cold (0° C.) solution of2-(2-fluoro-4-pyridinyl)-3-[2-(methylsulfanyl)-4-pyrimidinyl]pyrazolo[1,5-a]pyridine(1.81 g, 5.36 mmol) in dichloromethane (100 mL) was added3-chloroperoxybenzoic acid (1.39 g, 70%, 5.63 mmol). The reactionmixture was warmed to room temperature and stirred 16 hours. Thereaction mixture was diluted with 100 mL dichloromethane and washed withsaturated aqueous sodium bicarbonate solution. The organic layer wasconcentrated in vacuo to give 1.84 g of2-(2-fluoro-4-pyridinyl)-3-[2-(methylsulfinyl)-4-pyrimidinyl]pyrazolo[1,5-a]pyridineof 90% purity as a greenish grey solid. This material was carried onwithout further purification. ¹H NMR (DMSO-d₆) δ 8.92 (d, 1H), 8.75 (d,1H), 8.54 (d, 1H), 8.38 (d, 1H), 7.63-7.59 (m, 2H), 7.48 (s, 1H), 7.32(d, 1H), 7.24 (t, 1H), 2.87 (s, 3H); ¹⁹F NMR (DMSO-d₆) δ −68.05; MS m/z354 (M+1).

[0526] b)N-Cyclopropyl-4-[2-(2-fluoro-4-pyridinyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine.

[0527] A solution of2-(2-fluoro-4-pyridinyl)-3-[2-(methylsulfinyl)-4-pyrimidinyl]pyrazolo[1,5-a]pyridine(430 mg, 90%, ˜1.1 mmol) in cyclopropylamine (4 mL, 57.7 mmol) washeated at 45° C. in a sealed glass tube for 6 hours. The excesscyclopropylamine was removed in vacuo to provide crudeN-cyclopropyl-4-[2-(2-fluoro-4-pyridinyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine(370 mg, 97%). A small portion of the crude material was chromatographed(19:1 dichloromethane:acetone to 9:1 dichloromethane:acetone) to providematerial as a light yellow solid. R_(f) 0.26 (9:1dichloromethane:acetone); ¹H NMR (CDCl₃) δ 8.52 (d, 1H), 8.42 (d, 1H),8.29 (d, 1H), 8.21 (d, 1H), 7.51 (d, 1H), 7.36 (d, 1H), 7.32 (s, 1H),6.98 (t, 1H), 6.48 (d, 1H), 5.69 (br, 1H), 2.81 (m, 1H), 0.83 (m, 2H),0.61 (m, 2H); MS m/z 347 (M+1).

[0528] c)N-Cyclopropyl-4-{2-[2-(isopropylamino)-4-pyridinyl]pyrazolo[1,5-a]pyridin-3-yl}-2-pyrimidinamine.

[0529] A solution ofN-cyclopropyl-4-[2-(2-fluoro-4-pyridinyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine(206 mg, 0.595 mmol) in isopropylamine (3 mL, 35.2 mmol) was heated at150° C. in a steel bomb for 16 hours. The excess isopropylamine wasremoved under a stream of nitrogen. The crude material was trituratedwith ether to provideN-cyclopropyl-4-{2-[2-(isopropylamino)-4-pyridinyl]pyrazolo[1,5-a]pyridin-3-yl}-2-pyrimidinamine(185 mg, 80%) as a tan solid. ¹H NMR (CDCl₃) δ 8.60 (d, 1H), 8.51 (d,1H), 8.14 (m, 2H), 7.32 (t, 1H), 6.93 (t, 1H), 6.80 (d, 1H), 6.62 (s,1H), 6.55 (d, 1H), 5.62 (br, 1H), 4.60 (d, 1H), 3.87 (m, 1H), 2.85 (m,1H), 1.29 (d, 3H), 1.22 (d, 3H), 0.86 (m, 2H), 0.63 (m, 2H); MS m/z 386(M+1).

[0530] d)3-[2-(Cyclopropylamino)-4-pyrimidinyl]-N-isopropyl-2-[2-(isopropylamino)-4-pyridinyl]pyrazolo[1,5-a]pyridin-7-amine.

[0531] To a cold (−78° C.) solution ofN-cyclopropyl-4-{2-[2-(isopropylamino)-4-pyridinyl]pyrazolo[1,5-a]pyridin-3-yl}-2-pyrimidinamine(178 mg, 0.462 mmol) in tetrahydrofuran (15 mL) was added n-butyllithium(866 μL, 1.6 M in hexanes, 1.39 mmol) dropwise. The reaction mixture wasstirred at −78° C. for 30 minutes, then carbon tetrachloride (179 μL,1.85 mmol) was added dropwise. The resultant mixture was warmed to roomtemperature and stirred 2 hours. The reaction mixture was quenched withwater and diluted with ethyl acetate. The organic layer was washed withwater and brine, then dried over magnesium sulfate. Filtration andconcentration provided crude4-{7-chloro-2-[2-(isopropylamino)-4-pyridinyl]pyrazolo[1,5-a]pyridin-3-yl}-N-cyclopropyl-2-pyrimidinamine.This material was taken up in isopropylamine (3 mL, 35.2 mmol) andheated in a steel bomb at 120° C. for 16 hours. The reaction mixture wascooled and the excess isopropylamine was removed under a stream ofnitrogen. Preparative HPLC provided3-[2-(cyclopropylamino)-4-pyrimidinyl]-N-isopropyl-2-[2-(isopropylamino)-4-pyridinyl]pyrazolo[1,5-a]pyridin-7-amine(10 mg, 5%) as a yellow solid. ¹H NMR (CDCl₃) δ 8.10-8.07 (m, 2H), 7.87(d, 1H), 7.35 (t, 1H), 6.85 (d, 1H), 6.69 (s, 1H), 6.51 (d, 1H), 6.06(d, 1H), 5.94 (d, 1H), 5.68 (br, 1H), 4.16 (br, 1H), 3.93-3.79 (m, 2H),2.85 (m, 1H), 1.40 (d, 6H), 1.25 (d, 6H), 0.87 (m, 2H), 0.64 (m, 2H); MSm/z 443 (M+1).

EXAMPLE 18N-Cyclopentyl-2-[2-(cyclopentylamino)-4-pyridinyl]-3-[2-(isopropylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine

[0532]

[0533] a)4-[2-(2-Fluoro-4-pyridinyl)pyrazolo[1,5-a]pyridin-3-yl]-N-isopropyl-2-pyrimidinamine.To a cold (0° C.) solution of2-(2-fluoro-4-pyridinyl)-3-[2-(methylsulfanyl)-4-pyrimidinyl]pyrazolo[1,5-a]pyridine(200 mg, 0.59 mmol) in dichloromethane (10 mL) was addedm-chloroperoxybenzoic acid (154 mg, 70%, 0.62 mmol). The reactionmixture was warmed to room temperature and stirred 16 hours. Thereaction mixture was diluted with dichloromethane and washed withsaturated aqueous sodium bicarbonate solution. The organic layer wasconcentrated in vacuo to provide a green foam, which was dissolved inisopropylamine and heated in a sealed glass pressure tube at 45° C. for16 hours. The reaction mixture was cooled and the excess isopropylaminewas removed under a stream of nitrogen to provide crude4-[2-(2-fluoro-4-pyridinyl)pyrazolo[1,5-a]pyridin-3-yl]-N-isopropyl-2-pyrimidinamine(204 mg, 99%). R_(f) 0.25 (9:1 dichloromethane:acetone); MS m/z 349(M+1).

[0534] b)N-Cyclopentyl-N-(4-{3-[2-(isopropylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}-2-pyridinyl)amine.

[0535] A solution of crude4-[2-(2-fluoro-4-pyridinyl)pyrazolo[1,5-a]pyridin-3-yl]-N-isopropyl-2-pyrimidinamine(204 mg, 0.586 mmol) in cyclopentylamine (2 mL, 20.3 mmol) was heated at135° C. in a sealed glass tube for 16 hours. The reaction mixture wascooled and the excess cyclopentylamine was removed in vacuo. Theresultant residue was partitioned between ethyl acetate and saturatedaqueous sodium bicarbonate solution. The organic layer was washed withbrine and dried over magnesium sulfate. Filtration and concentration,followed by flash chromatography (1:1 hexanes:ethyl acetate to 100%ethyl acetate) providedN-cyclopentyl-N-(4-{3-[2-(isopropylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}-2-pyridinyl)amine(155 mg, 64%). R_(f) 0.16 (1:2 hexanes:ethyl acetate); ¹H NMR (CDCl₃) δ8.49 (d, 1H), 8.39 (d, 1H), 8.13-8.08 (m, 2H), 7.29 (t, 1H), 6.89 (t,1H), 6.80 (d, 1H), 6.63 (s, 1H), 6.46 (d, 1H), 5.23 (br, 1H), 4.86 (d,1H), 4.21 (m, 1H), 3.93 (m, 1H), 1.95 (m, 2H), 1.70-1.42 (m, 6H), 1.27(d, 6H); MS m/z 414 (M+1).

[0536] c)4-{7-Chloro-2-[2-(cyclopentylamino)-4-pyridinyl]pyrazolo[1,5-a]pyridin-3-yl}-N-isopropyl-2-pyrimidinamine.

[0537] In a similar manner as described in Example 17 fromN-cyclopentyl-N-(4-{3-[2-(isopropylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}-2-pyridinyl)amine(155 mg, 0.375 mmol), n-butyllithium (700 μL, 1.6 M in hexanes, 1.12mmol), and carbon tetrachloride (145 μL, 1.50 mmol) was formed4-{7-chloro-2-[2-(cyclopentylamino)-4-pyridinyl]pyrazolo[1,5-a]pyridin-3-yl}-N-isopropyl-2-pyrimidinamine.Flash chromatography (1:1 hexanes:ethyl acetate to 1:2 hexanes:ethylacetate) provided sample (65 mg, 39%). R_(f) 0.20 (1:1 hexanes:ethylacetate); ¹H NMR (CDCl₃) δ 8.40 (d, 1H), 8.14-8.11 (m, 2H), 7.27 (m,1H), 7.07 (d, 1H), 6.82 (d, 1H), 6.66 (s, 1H), 6.46 (d, 1H), 5.11 (d,1H), 4.79 (d, 1H), 4.21 (m, 1H), 3.98 (m, 1H), 1.98 (m, 2H), 1.74-1.44(m, 6H), 1.30 (d, 6H); MS m/z 448 (M+1).

[0538] d)N-Cyclopentyl-2-[2-(cyclopentylamino)-4-pyridinyl]-3-[2-(isopropylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine.

[0539] In a similar manner as described in Example 17 from4-{7-chloro-2-[2-(cyclopentylamino)-4-pyridinyl]pyrazolo[1,5-a]pyridin-3-yl}-N-isopropyl-2-pyrimidinamine(30 mg, 0.067 mmol) and cyclopentylamine (1 mL, 10 mmol) was formedN-cyclopentyl-2-[2-(cyclopentylamino)-4-pyridinyl]-3-[2-(isopropylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine(2 mg, 6%) as a yellow solid. R_(f) 0.22 (1:1 hexanes:ethyl acetate); ¹HNMR (CDCl₃) δ 8.09-8.05 (m, 2H), 7.70 (d, 1H), 7.34 (t, 1H), 6.86 (d,1H), 6.69 (s, 1H), 6.44 (d, 1H), 6.07 (d, 1H), 6.01 (d, 1H), 5.85 (br,1H), 5.20 (br, 1H), 4.21 (m, 1H), 4.02 (m, 1H), 3.93 (m, 1H), 2.15 (m,2H), 1.97 (m, 2H), 1.84-1.51 (m, 12H), 1.29 (d, 6H); MS m/z 497 (M+1).

EXAMPLE 193-[2-(Cyclopentylamino)-4-pyrimidinyl]-N-isopropyl-2-[2-(isopropylamino)-4-pyridinyl]pyrazolo[1,5-a]pyridin-7-amine

[0540]

[0541] a)N-Cyclopentyl-4-{2-[2-(isopropylamino)-4-pyridinyl]pyrazolo[1,5-a]pyridin-3-yl}-2-pyrimidinamine.In a similar manner as described in example 17 from2-(2-fluoro-4-pyridinyl)-3-[2-(methylsulfinyl)-4-pyrimidinyl]pyrazolo[1,5-a]pyridine(410 mg, 1.16 mmol) and cyclopentylamine (4 mL, 40.5 mmol) was formedcrudeN-cyclopentyl-4-[2-(2-fluoro-4-pyridinyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine(385 mg), of which 260 mg (0.694 mmol) was dissolved in isopropylamine(3 mL, 35.2 mmol) and heated at 150° C. in a steel bomb for 16 hours.The reaction mixture was cooled and the excess isopropylamine wasremoved under a stream of nitrogen to provideN-cyclopentyl-4-{2-[2-(isopropylamino)-4-pyridinyl]pyrazolo[1,5-a]pyridin-3-yl}-2-pyrimidinamine(170 mg, 52% for 2 step procedure) as a beige solid. ¹H NMR (CDCl₃) δ8.50 (d, 1H), 8.41 (d, 1H), 8.13-8.08 (m, 2H), 7.32 (t, 1H), 6.92 (t,1H), 6.80 (d, 1H), 6.62 (s, 1H), 6.47 (d, 1H), 5.26 (d, 1H), 4.63 (d,1H), 4.34 (m, 1H), 3.85 (m, 1H), 2.11-2.04 (m, 2H), 1.79-1.51 (m, 6H),1.22 (d, 6H); MS m/z 414 (M+1).

[0542] b)4-{7-Chloro-2-[2-(isopropylamino)-4-pyridinyl]pyrazolo[1,5-a]pyridin-3-yl}-N-cyclopentyl-2-pyrimidinamine.

[0543] In a similar manner as described in Example 17 fromN-cyclopentyl-4-{2-[2-(isopropylamino)-4-pyridinyl]pyrazolo[1,5-a]pyridin-3-yl}-2-pyrimidinamine(166 mg, 0.401 mmol), n-butyllithium (753 μL, 1.6 M in hexanes, 1.20mmol) and carbon tetrachloride (155 μL, 1.60 mmol) was formed4-{7-chloro-2-[2-(isopropylamino)-4-pyridinyl]pyrazolo[1,5-a]pyridin-3-yl}-N-cyclopentyl-2-pyrimidinamine(140 mg, 78%). R_(f) 0.21 (1:1 hexanes:ethyl acetate); ¹H NMR (CDCl₃) δ8.36 (d, 1H), 8.19 (d, 1H), 8.07 (d, 1H), 7.36 (m, 1H), 7.13 (d, 1H),6.90 (d, 1H), 6.81 (s, 1H), 6.52 (d, 1H), 5.25-5.21 (br, 2H), 4.35 (m,1H), 3.89 (m, 1H), 2.18-2.04 (m, 2H), 1.80-1.50 (m, 6H), 1.22 (d, 6H).

[0544] c)3-[2-(Cyclopentylamino)-4-pyrimidinyl]-N-isopropyl-2-[2-(isopropylamino)-4-pyridinyl]pyrazolo[1,5-a]pyridin-7-amine.

[0545] In a similar manner as described in Example 17 from4-{7-chloro-2-[2-(isopropylamino)-4-pyridinyl]pyrazolo[1,5-a]pyridin-3-yl}-N-cyclopentyl-2-pyrimidinamine(35 mg, 0.0781 mmol) and isopropylamine (2 mL, 23.5 mmol) was formed3-[2-(cyclopentylamino)-4-pyrimidinyl]-N-isopropyl-2-[2-(isopropylamino)-4-pyridinyl]pyrazolo[1,5-a]pyridin-7-amine(5 mg, 14%) as a yellow solid. R_(f) 0.22 (1:1 hexanes:ethyl acetate);¹H NMR (CDCl₃) δ 8.48 (s, 1H), 7.99 (s, 1H), 7.94 (d, 1H), 7.65 (d, 1H),7.36 (t, 1H), 6.84 (d, 1H), 6.75 (s, 1H), 6.45 (d, 1H), 6.07 (d, 1H),5.92 (d, 1H), 4.61 (br, 1H), 4.29 (m, 1H), 3.87 (m, 1H), 3.74 (m, 1H),2.04 (m, 2H), 1.76-1.55 (m, 6H), 1.39 (d, 6H), 1.25 (d. 6H); MS m/z 471(M+1).

EXAMPLE 20N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-[2-(isopropylamino)-4-pyridinyl]pyrazolo[1,5-a]pyridin-7-amine

[0546]

[0547] In a similar manner as described in Example 17 from4-{7-chloro-2-[2-(isopropylamino)-4-pyridinyl]pyrazolo[1,5-a]pyridin-3-yl}—N-cyclopentyl-2-pyrimidinamine(35 mg, 0.0781 mmol) and cyclopentylamine (2 mL) was formedN-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-[2-(isopropylamino)-4-pyridinyl]pyrazolo[1,5-a]pyridin-7-amine(15 mg, 38%). R_(f) 0.20 (39:1 dichloromethane:methanol); ¹H NMR (CDCl₃)δ 8.13 (d, 1H), 8.03 (d, 1H), 7.72 (d, 1H), 7.30 (t, 1H), 6.80 (d, 1H),6.60 (s, 1H), 6.42 (d, 1H), 6.03, (d, 1H), 5.99 (d, 1H), 5.13 (d, 1H),4.51 (d, 1H), 4.32 (m, 1H), 3.99 (m, 1H), 3.85 (m, 1H), 2.15-1.91 (m,4H), 1.81-1.50 (m, 12H), 1.21 (d, 6H); MS m/z 497 (M+1).

EXAMPLE 21N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyridinyl]-2-(2-furyl)pyrazolo[1,5-a]pyridin-7-amine

[0548]

[0549] a) 2-(6-Chloro-2-pyridinyl)-1-(2-furyl)ethanone.

[0550] The title compound was prepared from ethyl 2-furonate (6.3 g, 45mmol) and 6-chloropicoline (5.7 g, 45 mmol) as a mixture of ketone andenol tautomers in a similar manner as described in Example 1. Theproduct was purified by silica gel chromatography (3:1 hexane:ethylacetate) to give 2-(6-chloro-2-pyridinyl)-1-(2-furyl)ethanone (4.7g,47%) as a solid. ¹H NMR (CDCl₃) δ 8.02 (s, 1H), 7.82 (t, 1H), 7.57 (d,1H), 7.39 (d, 2H), 6.73 (m, 1H), 4.35 (s, 2H); MS m/z 222 (M+1).

[0551] b) 2-(6-Chloro-2-pyridinyl)-1-(2-furyl)ethanone oxime.

[0552] The title compound was prepared from2-(6-chloro-2-pyridinyl)-1-(2-furyl)ethanone (4.5 g, 20 mmol) in asimilar manner as described in example 1. The product was purified bysilica gel chromatography (4:1 hexane:ethyl acetate) to give2-(6-chloro-2-pyridinyl)-1-(2-furyl)ethanone oxime (2.7 g, 56%) as asolid. ¹H NMR (DMSO-d₆) δ 11.4 (s, 1H), 7.76-7.70 (m, 2H), 7.31 (d, 1H),7.19 (d, 1H), 6.75 (m, 1H), 6.52 (m, 1H), 4.1 (s, 2H); MS m/z 237 (M+1).

[0553] c) 7-Chloro-2-(2-furyl)pyrazolo[1,5-a]pyridine.

[0554] The title compound was prepared from2-(6-chloro-2-pyridinyl)-1-(2-furyl)ethanone oxime (2.7 g, 11 mmol) in asimilar manner as described in example 1. The product was purified bysilica gel chromatography (6:1 hexane:ethyl acetate) to give 1 g (40%)of 7-chloro-2-(2-furyl)pyrazolo[1,5-a]pyridine as a solid. ¹H NMR(CDCl₃) δ 7.55 (broad s, 1H), 7.49 (d, 1H), 7.08 (dd, 1H), 6.95 (d, 1H),6.90 (d, 1H), 6.86 (s, 1H), 6.51 (dd, 1H); MS m/z 219 (M+1).

[0555] d) 3-Bromo-7-chloro-2-(2-furyl)pyrazolo[1,5-a]pyridine.

[0556] 7-Chloro-2-(2-furyl)-pyrazolo[1,5-a]pyridine (0.23 g, 1.05 mmol)was dissolved in tetrahydrofuran (5 mL) and cooled to 0° C.N-Bromosuccinimide (0.19 g, 1.05 mmol) was added. The reaction wasstirred for 1 hour. The reaction solution was poured into equal volumes(10 mL) of saturated aqueous ammonium chloride and ether. The etherlayer was collected and the solvent removed in vacuo to give the crudeproduct. The product was purified by silica gel chromatography (6:1hexane:ethyl acetate) to give 0.3 g (96%) of3-bromo-7-chloro-2-(2-furyl)pyrazolo[1,5-a]pyridine as a solid. ¹H NMR(CDCl₃) δ 7.63 (d, 1H), 7.51 (d, 1H), 7.29 (d, 1H), 7.21 (dd, 1H), 6.98(d, 1H), 6.58 (dd, 1H); MS m/z 298 (M+1).

[0557] e)N-[3-Bromo-2-(2-furyl)pyrazolo[1,5-a]pyridin-7-yl]-N-cyclopentylamine.

[0558] 3-Bromo-7-chloro-2-(2-furyl)pyrazolo[1,5-a]pyridine (0.3 g, 1mmol) was dissolved in toluene (10 mL).2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (0.048 g, 0.06 mmol),palladium(II)acetate (0.01 g, 0.04 mmol) and cesium carbonate (0.82 g,2.6 mmol) was added. Cyclopropylamine (0.5 mL) was added and thereaction was heated in an 85° C. oil bath for 4 hours.2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (0.048 g, 0.06 mmol), andpalladium(II)acetate (0.01 g, 0.04 mmol) were added again and thereaction heated in a 105° C. oil bath for 4 hours. The reaction mixturewas poured into equal volumes (10 mL) of saturated aqueous ammoniumchloride and ether. The ether layer was collected and the solventremoved in vacuo to give the crude product. The product was purified bysilica gel chromatography (6:1 hexane:ethyl acetate) to give 0.25 g(72%) ofN-[3-bromo-2-(2-furyl)pyrazolo[1,5-a]pyridin-7-yl]-N-cyclopentylamine asa solid. ¹H NMR (CDCl₃) δ 7.6 (broad s, 1H), 7.24 (1H), 7.10 (m, 1H),6.86 (m, 1H), 6.57 (m, 1H), 5.94 (m, 1H), 4.0 (m, 1H), 2.19-2.09 (m,2H); 1.88-1.77 (m, 4H), 1.77-1.64 (m, 2H); MS m/z 345, 348 (M+1).

[0559] f) 2-Fluoropyridin-4-ylboronic acid.

[0560] To a stirred solution of n-butyl lithium (3.2 mL 2.5M, 8.0 mmol)in dry diethyl ether (20 mL) at −78° C. was added a solution of2-fluoro-4-iodopyridine (1.5 g, 6.7 mmol) in dry ether (10 mL) and thereaction mixture was stirred at −78° C. for 10 minutes. Tributyl borate(2.4 mL, 2.01 g, 8.7 mmol) was added and the reaction mixture wasallowed to warm to room temperature over 2 hours. Water (5 mL) was addedfollowed by 2N aqueous sodium hydroxide solution (10 mL) to dissolve thesolids. The organic phase was separated. The aqueous phase was acidifiedto pH 3 using 6N hydrochloric acid and the resulting white solid wascollected by filtration and dried under vacuum to give the titlecompound, 0.74 g (78%). ¹H NMR (DMSO-d₆) δ 8.65 (broad s, 2H), 8.21 (d,1H), 7.59 (t, 1H), 7.37 (d, 1H).

[0561] g)N-Cyclopentyl-3-(2-fluoro-4-pyridinyl)-2-(2-furyl)pyrazolo[1,5-a]pyridin-7-amine.

[0562]N-[3-Bromo-2-(2-furyl)pyrazolo[1,5-a]pyridin-7-yl]-N-cyclopentylamine(0.2 g, 0.6 mmol) was dissolved in N,N-dimethylformamide (8 mL). To thissolution was added 2-fluoro-4-pyridinylboronic acid (0.09 g, 0.64 mmol),dichlorobis(triphenylphosphine)palladium (II) (0.020 g, 0.03 mmol) andsaturated aqueous sodium carbonate (580 μl). The resulting solution washeated in a 75° C. oil bath overnight. Water was added to the reactionmixture and the product was extracted with ethyl acetate. The organicphase was dried (magnesium sulfate), filtered and concentrated to asolid. The product was purified by silica gel chromatography (7:1hexane:ethyl acetate) to give 50 mg (24%) ofN-cyclopentyl-3-(2-fluoro-4-pyridinyl)-2-(2-furyl)pyrazolo[1,5-a]pyridin-7-amineas a solid. ¹H NMR (CDCl₃) δ 8.1 (d, 1H), 7.5 (s, 1H), 7.24 (1H),7.03(s, 1H), 6.96 (d, 1H), 6.75 (d, 1H), 6.5 (m, 1H), 6.01 (m, 2H), 4.0(m, 1H), 2.19-2.09 (m, 2H); 1.88-1.77 (m, 4H), 1.77-1.64 (m, 2H); MS m/z363 (M+1).

[0563] h)N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyridinyl]-2-(2-furyl)pyrazolo[1,5-a]pyridin-7-amine.

[0564]N-Cyclopentyl-3-(2-fluoro-4-pyridinyl)-2-(2-furyl)pyrazolo[1,5-a]pyridin-7-amine(0.05 g, 0.02 mmol) was dissolved in cyclopentylamine (1 mL and heated)in a 135° C. oil bath for 4 days. The amine was removed in vacuo. Theproduct was purified by silica gel chromatography (7:1 hexane:ethylacetate) to give 25 mg (42%) ofN-cyclopentyl-3-[2-(cyclopentylamino)-4-pyridinyl]-2-(2-furyl)pyrazolo[1,5-a]pyridin-7-amine.¹H NMR (CDCl₃) δ 8.1 (d, 1H), 7.51 (s, 1H), 7.17 (t, 1H), 6.94 (d, 1H),6.69 (m, 2H), 6.5 (s, 1H), 6.45 (m, 1H), 6.00 (d, 1H). 5.95 (d, 1H), 4.6(br d, 1H), 4.0 (m, 1H), 3.92 (m, 1H), 2.19-2.09 (m, 2H), 2.03-1.95 (m,2H), 1.88-1.43 (m, 8H), 1.32-1.22 (m, 2H); MS m/z 428 (M+1).

EXAMPLE 22N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(3-methyl-2-furyl)pyrazolo[1,5-a]pyridin-7-amine

[0565]

[0566] a) 2-(6-Chloro-2-pyridinyl)-1-(3-methyl-2-furyl)ethanone.

[0567] To a cold (0° C.) solution of 6-chloro-2-picoline (25.8 mL 236mmol) and methyl 3-methyl-2-furoate (33.08 g, 236 mmol) intetrahydrofuran (300 mL) was added lithium bis(trimethylsilyl)amide (472mL, 1.0 M in tetrahydrofuran, 472 mmol) dropwise via a pressureequalizing funnel over 1 hour. Upon complete addition, the cold bath wasremoved and the resultant solution was stirred at room temperature for15 hours. The solution was concentrated. Methanol was added to quenchthe reaction resulting in a yellow solid precipitating. The precipitatewas collected by filteration and washed with a small amount of coldmethanol. 2-(6-Chloro-2-pyridinyl)-1-(3-methyl-2-furyl)ethanone (52.2 g,94%) was obtained as a yellow solid. ¹H NMR (CDCl₃): δ 7.61 (t, 1H),7.43 (s, 1H), 7.23 (m, 2H), 6.40 (s, 1H), 4.36 (s, 2H), 2.37 (s, 3H). MSm/z 236 (M+1).

[0568] b) 2-(6-Chloro-2-pyridinyl)-1-(3-methyl-2-furyl)ethanone oxime.

[0569] To a solution of2-(6-chloro-2-pyridinyl)-1-(3-methyl-2-furyl)ethanone (52.2 g, 221 mmol)in methanol (500 mL) was added hydroxylamine hydrochloride (76.96 g,1.11 mol) followed by an aqueous solution of sodium hydroxide (44.3 g,1.11 mol). The resultant suspension was heated at reflux for 2 hours andthen cooled to room temperature. The mixture was concentrated and waterwas added to the residue while stirring. After stirring for 20 minutes,a white solid precipitated. This solid was collected by filtration andwashed with water to give2-(6-chloro-2-pyridinyl)-1-(3-methyl-2-furyl)ethanone oxime (29.0 g,52%) as a white solid. ¹H NMR (CDCl₃): δ 7.54 (t, 1H), 7.31 (s, 1H),7.15 (d, 1H), 7.10 (d, 1H), 6.28 (s, 1H), 4.34 (s, 2H), 2.22 (s, 3H). MSm/z 273 (M+1).

[0570] c) 7-Chloro-2-(3-methyl-2-furyl)pyrazolo[1,5-a]pyridine.

[0571] To a solution of2-(6-chloro-2-pyridinyl)-1-(3-methyl-2-furyl)ethanone oxime (24.5 g,97.7 mmol) in 1,2-dimethoxyethane (200 mL) at 0° C. was addedtrifluoroacetic anhydride (14.5 mL, 103 mmol), while keeping thetemperature below 10° C. After the addition was complete, the reactionwas warmed to 15° C. The solution was then cooled to 0-5° C. and asolution of triethylamine (28.6 mL, 205 mmol) in 1,2-dimethoxyethane (30mL) was added over 0.5 hours. The reaction mixture was allowed to warmto room temperature and was stirred for 2 hours. To this mixture wasadded iron(II) chloride (0.62 g, 4.9 mmol) and the reaction was heatedat 75° C. for 15 hours. The reaction was concentrated, then ethylacetate and water were added. The organic phase was separated, washedwith water, dried (magnesium sulfate), filtered and concentrated.Purification by silica gel chromatography (9:1 hexanes:ethyl acetate)gave 7-chloro-2-(3-methyl-2-furyl)pyrazolo[1,5-a]pyridine (14.6 g, 64%)as yellow oil. ¹H NMR (CDCl₃): δ 7.52 (d, 1H), 7.48 (d, 1H), 7.10 (t,1H), 6.92 (d, 1H), 6.86 (s, 1H), 6.42 (d, 1H), 2.49 (s, 3H). MS m/z 233(M+1).

[0572] d)7-Chloro-2-(3-methyl-2-furyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde.

[0573] A dry flask charged with dry N,N-dimethylformamide (100 mL) wastreated with phosphorous oxychloride (8.8 mL, 94 mmol). The resultantsolution was stirred at room temperature for 1 hour.7-Chloro-2-(3-methyl-2-furyl)pyrazolo[1,5-a]pyridine (14.6 g, 63 mmol)was added and the reaction mixture was stirred for 2.5 hours. Water anddichloromethane were added to quench the reaction. The aqueous phase andorganic phase were separated. The aqueous phase was extracted withdichloromethane. The organics were combined and washed with water, driedover magnesium sulfate, filtered and the filtrate was concentrated.Crystallization from a small amount of methanol gave7-chloro-2-(3-methyl-2-furyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde(12.4 g, 76%) as a peach color crystalline compound. ¹H NMR (CDCl₃): δ10.58 (s, 1H), 8.43 (d, 1H), 7.58 (d, 1H), 7.48 (t, 1H), 7.21 (d, 1H),6.51 (d, 1H), 2.56 (s, 3H). MS m/z 261 (M+1).

[0574] e)1-[7-Chloro-2-(3-methyl-2-furyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol.

[0575] To a solution of7-chloro-2-(3-methyl-2-furyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde(11.56 g, 44.3 mmol) in tetrahydrofuran (200 mL) at −78° C. was addedethynylmagnesium bromide (133 mL, 0.5 M in tetrahydrofuran, 66.5 mmol).The mixture was allowed to warm to room temperature and stirred for 1hour. Water was added to the reaction and the resulting mixture wasextracted with ethyl acetate. The ethyl acetate phase was dried overmagnesium sulfate, filtered and concentrated to a solid residue,1-[7-chloro-2-(3-methyl-2-furyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol(12.29 g, 97%). ¹H-NMR (CDCl₃): δ 7.97 (d, 1H), 7.48 (d, 1H), 7.16 (t,1H), 6.96 (d, 1H), 6.42 (d, 1H), 6.18 (m, 1H), 2.78 (m, 1H), 2.6 (d,1H), 2.46 (s, 3H). MS m/z 287 (M+1).

[0576] f)1-[7-Chloro-2-(3-methyl-2-furyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one.

[0577]1-[7-Chloro-2-(3-methyl-2-furyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol(12.29 g, 42.9 mmol) was dissolved in dichloromethane (200 mL) andmanganese dioxide (112 g, 1.29 mol) was added. This slurry was stirredat room temperature for 2 hours. The manganese dioxide was removed byfiltration and the filtrate was concentrated to a solid. This solid waspurified by flash chromatography (dichloromethane) to give1-[7-chloro-2-(3-methyl-2-furyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one(7.53 g, 62%) as a white solid. ¹H-NMR (CDCl₃): δ 8.37 (d, 1H), 7.48 (m,2H), 7.19 (d, 1H), 6.41 (d, 1H), 3.12 (s, 1H), 2.20 (s, 3H). MS m/z 285(M+1).

[0578] g)4-[7-Chloro-2-(3-methyl-2-furyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine.

[0579] Sodium ethylate solution (21% T, 0.5 mL, 1.43 mmol) was added toethanol followed by cyclopentylguanidine hydrochloride (323 mg, 1.98mmol). The mixture was stirred at room temperature for 30 minutes.1-[7-Chloro-2-(3-methyl-2-furyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one(313 mg, 1.10 mmol) was added to the resultant solution and stirred atroom temperature for 15 hours. The reaction mixture was concentrated.Ethyl acetate and water were added to the residue. The phases wereseparated, the organic phase dried (magnesium sulfate), filtered andconcentrated. The residue was recrystallized from ethyl acetate.4-[7-Chloro-2-(3-methyl-2-furyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine(280 mg, 65%) was obtained as a yellow solid. ¹H-NMR (CDCl₃): δ 8.50 (d,1H), 8.15 (d, 1H), 7.49 (d, 1H), 7.27 (t, 1H), 7.06 (d, 1H), 6.41 (d,1H), 6.36 (d, 1H), 5.10 (d, 1H), 4.35 (m, 1H), 2.12 (s, 3H), 2.08 (m,2H), 1.78-1.53 (m, 6H). MS m/z 394 (M+1).

[0580] h)N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(3-methyl-2-furyl)pyrazolo[1,5-a]pyridin-7-amine.

[0581] To a solution of4-[7-chloro-2-(3-methyl-2-furyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine(150 mg, 0.38 mmol) in cyclopentylamine (10 mL) was addedracemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (76 mg, 0.12 mmol),cesium carbonate (247 mg, 0.76 mmol) and palladium (II) acetate (17 mg,0.076 mmol). The resulting mixture was stirred at 100° C. for 3 hours.Water was added and the mixture was extracted with ethyl acetate. Theethyl acetate phase was washed with brine, dried over magnesium sulfate,filtered and concentrated in vacuo. The resulting residue was purifiedby flash chromatography (3:7 ethyl acetate:hexane) to give 147 mg (87%)ofN-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(3-methyl-2-furyl)pyrazolo[1,5-a]pyridin-7-amineas a yellow solid. ¹H-NMR (CDCl₃): δ 8.07 (d, 1H), 7.85 (d, 1H), 7.50(d, 1H), 7.31 (t, 1H), 6.42 (d, 1H), 6.25 (d, 1H), 6.04 (d, 1H), 6.00(d, 1H), 5.06 (d, 1H), 4.36 (m, 1H), 3.98 (m, 1H), 2.08 (m, 4H), 2.05(s, 3H), 1.81-1.52 (m, 12H). MS m/z 443 (M+1).

EXAMPLE 23N-Cyclopentyl-3-[2-(cyclopropylamino)-4-pyrimidinyl]-2-(3-methyl-2-furyl)pyrazolo[1,5-a]pyridin-7-amine

[0582]

[0583] a)4-[7-Chloro-2-(3-methyl-2-furyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropyl-2-pyrimidinamine.In a similar manner described in Example 22 from1-[7-chloro-2-(3-methyl-2-furyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one(500 mg, 1.76 mmol) was obtained4-[7-chloro-2-(3-methyl-2-furyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropyl-2-pyrimidinamine(182 mg, 28%) as a pale yellow solid. ¹H-NMR (CDCl₃): δ 8.66 (broad d,1H), 8.18 (d, 1H), 7.48 (d, 1H), 7.22 (t, 1H), 7.03 (d, 1H), 6.41 (m,2H), 5.75 (s, 1H), 2.81 (m, 1H), 2.12 (s, 3H), 0.80 (m, 2H), 0.59 (m,2H). MS m/z 366 (M+1).

[0584] b)N-Cyclopentyl-3-[2-(cyclopropylamino)-4-pyrimidinyl]-2-(3-methyl-2-furyl)pyrazolo[1,5-a]pyridin-7-amine.

[0585] In the similar manner as described in Example 22 from4-[7-chloro-2-(3-methyl-2-furyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropyl-2-pyrimidinamine(80 mg, 0.22 mmol) was obtainedN-cyclopentyl-3-[2-(cyclopropylamino)-4-pyrimidinyl]-2-(3-methyl-2-furyl)pyrazolo[1,5-a]pyridin-7-amine(20 mg, 21%) as a yellow foam. ¹H-NMR (CDCl₃): δ 8.12 (d, 1H), 8.01 (d,1H), 7.51 (d, 1H), 7.31 (t, 1H), 6.43 (d, 1H), 6.32 (d, 1H), 6.05 (d,1H), 6.00 (d, 1H), 5.35 (s, 1H), 4.00 (m, 1H), 2.87 (m, 1H), 2.13 (m,2H), 2.06 (s, 3H), 1.81-1.66 (m, 6H), 0.86 (m, 2H), 0.62 (m, 2H). MS m/z415 (M+1).

EXAMPLE 24N-Cyclopropyl-3-[2-(cyclopropylamino)-4-pyrimidinyl]-2-(3-methyl-2-furyl)pyrazolo[1,5-a]pyridin-7-amine

[0586]

[0587] In a similar manner as described in Example 22 from4-[7-chloro-2-(3-methyl-2-furyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropyl-2-pyrimidinamine(92 mg, 0.25 mmol) was obtainedN-cyclopropyl-3-[2-(cyclopropylamino)-4-pyrimidinyl]-2-(3-methyl-2-furyl)pyrazolo[1,5-a]pyridin-7-amine(75 mg, 77%) as a yellow solid. ¹H-NMR (CDCl₃): δ 8.17 (d, 1H), 8.12 (d,1H), 7.54 (d, 1H), 7.38 (t, 1H), 6.46-6.36 (m, 4H), 5.44 (s, 1H), 2.89(m, 1H), 2.70 (m, 1H), 2.09 (s, 3H), 0.91 (m, 4H), 0.77 (m, 2H), 0.66(m, 2H). MS m/z 387 (M+1).

EXAMPLE 25N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(2-furyl)pyrazolo[1,5-a]pyridin-7-amine

[0588]

[0589] a) 7-Chloro-2-(2-furyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde.

[0590] A dry flask charged with dry N,N-dimethylformamide (100 mL) wastreated with phosphorous oxychloride (6.0 mL 64.5 mmol). The resultantsolution was stirred at room temperature for 1 hour.7-Chloro-2-(2-furyl)pyrazolo[1,5-a]pyridine (9.4 g, 43 mmol, example 21)was added to the previous solution and stirred for 2.5 hours. Water anddichloromethane were added to quench the reaction. The aqueous phase andorganic phase were separated. The aqueous phase was extracted withdichloromethane. The organics were combined and washed with water, driedover magnesium sulfate, filtered and concentrated. Crystallization froma small amount of methanol gave7-chloro-2-(2-furyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde (8.4 g, 79%)as pale yellow crystalline compound. ¹H NMR (CDCl₃): δ 10.57 (s, 1H),8.41 (d, 1H), 7.71 (d, 1H), 7.51 (t, 1H), 7.27 (d, I1H), 7.22 (d, 1H),6.66 (m, 1H). MS m/z 247 (M+1).

[0591] b)1-[7-Chloro-2-(2-furyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol.

[0592] To a solution of7-chloro-2-(2-furyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde (3.36 g, 13.6mmol) in tetrahydrofuran (100 mL) at −78° C. was added ethynylmagnesiumbromide (32.7 mL, 0.5 M in tetrahydrofuran, 16.3 mmol). The mixture wasallowed to warm to room temperature and stirred for 1 hour. Water wasadded to the reaction and the resulting mixture was extracted with ethylacetate. The ethyl acetate phase was dried over magnesium sulfate,filtered and concentrated to a solid residue,1-(7-chloro-2-(2-furyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol (3.63g, 98%). ¹H NMR (CDCl₃): δ 7.98 (d, 1H), 7.59 (d, 1H), 7.16 (t, 1H),7.03 (d, 1H), 6.95 (d, 1H), 6.55 (m, 1H), 6.16 (m, 1H), 2.76 (m, 1H),2.63 (s, 1H). MS m/z 273 (M+1).

[0593] c)1-[7-Chloro-2-(2-furyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one.

[0594] 1-[7-Chloro-2-(2-furyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol(3.63 g, 13.3 mmol) was dissolved in dichloromethane (200 mL) andmanganese dioxide (34.7 g, 399 mmol) was added. This slurry was stirredat room temperature for 2 hours. The manganese dioxide was removed byfiltration and the filtrate was concentrated to a solid,1-[7-chloro-2-(3-methyl-2-furyl)pyrazolo[115-a]pyridin-3-yl]-2-propyn-1-one (1.99 g, 55%). ¹H NMR (CDCl₃): δ 8.54(d, 1H), 7.65 (d, 1H), 7.62 (d, 1H), 7.49 (t, 1H), 7.21 (d, 1H), 6.58(m, 1H), 3.35 (s, 1H). MS m/z 271 (M+1).

[0595] d)4-[7-Chloro-2-(2-furyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine.

[0596] Cyclopentylguanidine hydrochloride (1.53 g, 9.38 mmol) andpotassium carbonate (0.78 g, 5.63 mmol) were added to 80 mL of ethanol.The suspension was stirred at room temperature for 1 hour.1-[7-Chloro-2-(2-furyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one (1.27g, 4.69 mmol) was added to the resultant solution and stirred at roomtemperature for 24 hours. The reaction mixture was concentrated andethyl acetate and water were added. The phases were separated, theorganic phase was dried over magnesium sulfate, filtered andconcentrated. Purification by flash chromatography (3:7 ethylacetatehexanes). gave4-[7-Chloro-2-(2-furyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine(520 mg, 30%) as a yellow solid. ¹H NMR (CDCl₃): δ 8.28 (d, 1H), 8.22(d, 1H), 7.58 (d, 1H), 7.23 (m, 1H), 7.04 (d, 1H), 6.92 (d, 1H), 6.62(d, 1H), 6.53 (m, 1H), 5.16 (d, 1H), 4.35 (m, 1H), 2.07 (m, 2H),1.77-1.52 (m, 6H). MS m/z 380 (M+1).

[0597] e)N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(2-furyl)pyrazolo[1,5-a]pyridin-7-amine.

[0598]4-[7-Chloro-2-(2-furyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine(200 mg, 0.53 mmol) was dissolved in 5 mL of cyclopentylamine. Thesolution was heated at 100° C. overnight, then cooled to roomtemperature. Ethyl acetate was added to dilute the reaction mixture, theorganic phase was washed with water and brine and dried over magnesiumsulfate. Filtration and concentration followed by purification withflash chromatography (1:4 ethyl acetate:hexanes) gaveN-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(2-furyl)pyrazolo[1,5-a]pyridin-7-amine(206 mg, 91%) as a yellow solid. ¹H NMR (CDCl₃): δ 8.20 (d, 1H), 7.68(d, 1H), 7.62 (d, 1H), 7.32 (t, 1H), 6.92 (d, 1H), 6.59 (m, 2H), 6.05(m, 2H), 5.11 (d, 1H), 4.43 (m, 1H), 4.04 (m, 1H), 2.14 (m, 4H),1.87-1.56 (m, 12H). MS m/z 429 (M+1).

EXAMPLE 263-[2-(Cyclopentylamino)-4-pyrimidinyl]-N-cyclopropyl-2-(2-furyl)pyrazolo[1,5-a]pyridin-7-amine

[0599]

[0600]4-[7-Chloro-2-(2-furyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentil-2-pyrimidinamine

[0601] (100 mg, 0.26 mmol) and cyclopropylamine (5 mL) were put in asteel bomb. After heating at 100° C. for 3 days, the reaction wasallowed to cool to room temperature. The reaction mixture was dilutedwith ethyl acetate, washed with water and brine, then dried overmagnesium sulfate. Filtration and concentration followed by purificationwith flash chromatography (3:7 ethyl acetate:hexanes) gave3-[2-(cyclopentylamino)-4-pyrimidinyl]-N-cyclopropyl-2-(2-furyl)pyrazolo[1,5-a]pyridin-7-amine(34 mg, 32%) as a yellow foam. ¹H NMR (CDCl₃): δ 8.15 (d, 1H), 7.67 (d,1H), 7.56 (d, 1H), 7.30 (t, 1H), 6.86 (d, 1H), 6.57 (d, 1H), 6.52 (m,1H), 6.36 (d, 1H), 6.32 (s, 1H), 5.14 (d, 1H), 4.36 (m, 1H), 2.63 (m,1H), 2.08 (m, 2H), 1.76-1.52 (m, 6H), 0.86 (m, 2H), 0.75 (m, 2H). MS m/z401 (M+1).

EXAMPLE 272-(5-Bromo-2-furyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine

[0602]

[0603] a)2-(5-Bromo-2-furyl)-7-chloropyrazolo[1,5-a]pyridine-3-carbaldehyde.

[0604] To a solution of7-chloro-2-(2-furyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde (2.0 g, 8.06mmol) in dichloromethane was added N-bromosuccinimide (2.01 g, 11.28mmol). After stirring at room temperature for 2 hours, the reactionmixture was diluted with dichloromethane, washed with water and brineand dried over magnesium sulfate. Filtration and concentration followedby recrystallization with ethyl acetate gave2-(5-bromo-2-furyl)-7-chloropyrazolo[1,5-a]pyridine-3-carbaldehyde (2.1g, 80%) as a white solid. ¹H NMR (CDCl₃): δ 10.50 (s, 1H), 8.37 (dd,1H), 7.47 (t, 1H), 7.20-7.18 (m, 2H), 6.54 (d, 1H). MS m/z 325 (M+1).

[0605] b)1-[2-(5-Bromo-2-furyl)-7-chloropyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one.

[0606] In a similar manner as described in Example 25 from2-(5-bromo-2-furyl)-7-chloropyrazolo[1,5-a]pyridine-3-carbaldehyde (2.54g, 7.8 mmol) was obtained1-[2-(5-bromo-2-furyl)-7-chloropyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol.To the solution of1-[2-(5-bromo-2-furyl)-7-chloropyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-olin dichloromethane was added manganese dioxide as described in example25.1-[2-(5-Bromo-2-furyl)-7-chloropyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one(0.86 g, two steps 32%) was obtained as a yellow solid. ¹H NMR (CDCl₃):δ 8.53 (d, 1H), 7.52-7.48 (m, 2H), 7.22 (d, 1H), 6.51 (d, 1H), 3.36 (s,1H). MS m/z 349 (M+1).

[0607] c)4-[2-(5-Bromo-2-furyl)-7-chloropyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine.In a similar manner as described in example 25 from1-[2-(5-bromo-2-furyl)-7-chloropyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one(0.85 g, 2.43 mmol) was obtained4-[2-(5-bromo-2-furyl)-7-chloropyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine(0.81 g, 73%) as a pale yellow solid. ¹H NMR (CDCl₃): δ 8.24 (m, 2H),7.25 (t, 1H), 7.05 (dd, 1H), 6.88 (d, 1H), 6.66 (d, 1H), 6.46 (d, 1H),5.15 (d, 1H), 4.35 (m, 1H), 2.07 (m, 2H), 1.77-1.52 (m, 6H). MS m/z 458(M+1).

[0608] d)2-(5-Bromo-2-furyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine.In a similar manner as described in example 25 from4-[2-(5-bromo-2-furyl)-7-chloropyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine(200 mg, 0.56 mmol) was obtained2-(5-bromo-2-furyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine(190 mg, 86%) as a yellow foam. ¹H NMR (CDCl₃): δ 8.16 (d, 1H), 7.56 (d,1H), 7.28 (t, 1H), 6.83 (d, 1H), 6.62 (d, 1H), 6.45 (d, 1H), 6.04 (d,1H), 6.01 (d, 1H), 5.20 (b, 1H), 4.37 (m, 1H), 4.00 (m, 1H), 2.18-2.04(m, 4H), 1.84-1.55 (m, 12H). MS m/z 507 (M+1).

EXAMPLE 28N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyridinyl]-2-(2-methyl-1,3-thiazol-4-yl)pyrazolo[1,5-a]pyridin-7-amine

[0609]

[0610] a) 4-(2-Fluoro-4-pyridinyl)-3-butyn-2-ol.

[0611] A solution of 2-fluoro-4-iodopyridine (3.0 g, 13 mmol),3-butyn-2-ol (2.1 mL, 26 mmol), dichlorobis(triphenylphosphine)palladium (II) (0.9 g, 1.3 mmol), copper (I) iodide (0.5 g, 2.6 mmol),triethylamine (5.4 mL 39 mmol), and anhydrous N,N-dimethylformamide (20mL) were heated to 75° C. for 4 hours. When judged to be complete, themixture was partitioned between ethyl acetate and water, the organicswere washed with brine, dried over magnesium sulfate, filtered andconcentrated. The crude mixture was purified using flash chromatography(4:1 hexanes: ethyl acetate) to provide4-(2-fluoro-4-pyridinyl)-3-butyn-2-ol (1.4 g, 66%) as an orange oil. ¹HNMR (DMSO-d₆): δ 8.21 (d, 1H), 7.32 (d, 1H), 7.20 (s, 1H), 5.62 (d, 1H),4.61 (m, 1H), 1.36 (d, 3H).

[0612] b)1-[3-(2-Fluoro-4-pyridinyl)pyrazolo[1,5-a]pyridin-2-yl]ethanol.

[0613] A solution of 4-(2-fluoro-4-pyridinyl)-3-butyn-2-ol (1.4 g, 8.5mmol), aminopyridinium iodide (2.2 g, 9.8 mmol),1,8-diazobicyclo[5.4.0]undec-7-ene (1.9 mL, 12.7 mmol), and acetonitrile(20 mL) were allowed to stir for 12-16 hours at room temperature. Whenjudged to be complete, the mixture was partitioned between ethyl acetateand water, the organics were washed with brine, dried over magnesiumsulfate, filtered and suspended onto silica gel. The crude material waspurified by flash chromatography (1:1 hexanes:ethyl acetate) to provide1-[3-(2-fluoro-4-pyridinyl)pyrazolo[1,5-a]pyridin-2-yl]ethanol (1.0 g,46%) as a beige solid. ¹H NMR (DMSO-d₆): δ 8.79 (d, 1H), 8.30 (d, 1H),7.87 (d, 1H), 7.67 (d, 1H), 7.50 (s, 1H), 7.41 (m, 1H), 7.04 (m, 1H),5.57 (m, 1H), 5.03 (m, 1H), 1.56 (d, 3H).

[0614] c)1-[3-(2-Fluoro-4-pyridinyl)pyrazolo[1,5-a]pyridin-2-yl]ethanone.

[0615] A solution of1-[3-(2-fluoro-4-pyridinyl)pyrazolo[1,5-a]pyridin-2-yl]ethanol (0.1 g,0.4 mmol), manganese(IV)oxide (0.17 g, 1.95 mmol), and methylenechloride (10 mL) were allowed to stir at room temperature for 72 hours.When judged to be complete, the mixture was filtered through a plug ofCelite, and the filtrate was concentrated to provide1-[3-(2-fluoro-4-pyridinyl)pyrazolo[1,5-a]pyridin-2-yl]ethanone (97 mg,98%) as a pale yellow solid. ¹H NMR (DMSO-d₆): δ 8.92 (d, 1H), 8.30 (d,1H), 7.82 (d, 1H), 7.46 (m, 2H), 7.34 (s, 1H), 7.23 (m, 1H), 2.71 (s,3H).

[0616] d)2-Bromo-1-[3-(2-fluoro-4-pyridinyl)pyrazolo[1,5-a]pyridin-2-yl]ethanone.

[0617] To a solution of1-[3-(2-fluoro-4-pyridinyl)pyrazolo[1,5-a]pyridin-2-yl]ethanone (580 mg,2.27 mmol) in acetic acid (20 mL) was added bromine (0.12 mL, 2.27mmol). After heating at 80° C. for 30 minutes, the solution was cooledto room temperature. Ethyl acetate was added to dilute the reactionmixture. The mixture was washed with water (×3), brine and dried overmagnesium sulfate. Filtration and concentration, followed byrecrystallization from ethyl acetate gave2-bromo-1-[3-(2-fluoro-4-pyridinyl)pyrazolo[1,5-a]pyridin-2-yl]ethanone(478 mg, 64%) as a yellow solid. ¹H NMR (CDCl₃): δ 8.51 (d, 1H), 8.27(d, 1H), 7.65 (d, 1H), 7.33 (m, 2H), 7.10 (s, 1H), 7.06 (t, 1H), 4.76(s, 2H). MS m/z 334 (M+1).

[0618] e)3-(2-Fluoro-4-pyridinyl)-2-(2-methyl-1,3-thiazol-4-yl)pyrazolo[1,5-a]pyridine.

[0619] To a solution of2-bromo-1-[3-(2-fluoro-4-pyridinyl)pyrazolo[1,5-a]pyridin-2-yl]ethanone(250 mg, 0.75 mmol) in N,N-dimethylformamide (15 mL) was addedthioacetamide (67 mg, 0.90 mmol). After heating at 60° C. for 3 hours,the reaction was cooled to room temperature. An ammonium hydroxidesolution was used to adjust the pH to 9. The resultant solution wasextracted with ethyl acetate. The organics were combined and washed withwater, brine and dried over magnesium sulfate. Filtration andconcentration gave3-(2-fluoro-4-pyridinyl)-2-(2-methyl-1,3-thiazol-4-yl)pyrazolo[1,5-a]pyridine(220 mg, 95%) as a pale yellow solid. ¹H NMR (CDCl₃): δ 8.56 (d, 1H),8.23 (d, 1H), 7.61 (d, 1H), 7.30 (s, 1H), 7.27 (m, 2H), 7.05 (s, 1H),6.89 (m, 1H), 2.76 (s. 3H). MS m/z 311 (M+1).

[0620] f)N-Cyclopentyl-4-[2-(2-methyl-1,3-thiazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyridinamine.

[0621] A solution of3-(2-fluoro-4-pyridinyl)-2-(2-methyl-1,3-thiazol-4-yl)pyrazolo[1,5-a]pyridine(220 mg, 0.71 mmol) and potassium carbonate (98 mg, 0.71 mmol) incyclopentylamine (5 mL) was heated at 100° C. for 12 days. After coolingto room temperature, the solution was diluted with ethyl acetate and theorganic phase was washed with water and brine, then dried over magnesiumsulfate. Filtration and concentration, followed by flash chromatography(1:9 methanol/chloroform) gaveN-cyclopentyl-4-[2-(2-methyl-1,3-thiazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyridinamine(265 mg, 100%) as an oil. ¹H NMR (CDCl₃): δ 8.49 (d, 1H), 8.04 (d, 1H),7.49 (d, 1H), 7.08 (t, 1H), 6.74 (t, 1H), 6.59 (d, 1H), 6.43 (s, 1H),5.44 (d, 1H), 3.79 (m, 1H), 2.73 (s, 3H), 1.92-1.42 (m, 8H). MS m/z 376(M+1).

[0622] g)4-[7-Chloro-2-(2-methyl-1,3-thiazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyridinamine.

[0623] A solution ofN-cyclopentyl-[2-(2-methyl-1,3-thiazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyridinamine(138 mg, 0.37 mmol) in tetrahydrofuran (10 mL) was cooled to −78° C.n-Butyl lithium (1.6M in hexanes, 0.75 mL, 1.22 mmol) was addeddropwise. After stirring at −78° C. for 20 minutes, carbon tetrachloride(1 mL) was added to the solution. The reaction was stirred for another20 minutes at −78° C. and subsequently quenched with water. The reactionmixture was warmed to room temperature and extracted with ethyl acetate.The organics were combined and washed with water, brine and dried overmagnesium sulfate. Filtration and concentration, followed by flashchromatography (1:19 methanol/dichloromethane) gave4-[7-chloro-2-(2-methyl-1,3-thiazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyridinamineas a brown oil.

[0624] h)N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyridinyl]-2-(2-methyl-1,3-thiazol-4-yl)pyrazolo[1,5-a]pyridin-7-amine.

[0625] To4-[7-chloro-2-(2-methyl-1,3-thiazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyridinaminefrom previous reaction was added cyclopentylamine and the resultingmixture heated to 80° C. for 3 days. The resultant solution was cooledto room temperature, diluted with ethyl acetate and washed with water,brine and dried over magnesium sulfate. Filtration and concentrationfollowed by flash chromatography (1:19 methanol/dichloromethane) gaveN-cyclopentyl-3-[2-(cyclopentylamino)-4-pyridinyl]-2-(2-methyl-1,3-thiazol-4-yl)pyrazolo[1,5-a]pyridin-7-amine(20 mg, 12% for two steps) as a brown foam. ¹H NMR (CDCl₃): δ 8.09 (d,1H), 7.56 (d, 1H), 7.34 (s, 1H), 7.15 (t, 1H), 6.98 (d, 1H), 6.64 (d,1H), 6.45 (s, 1H), 5.60 (d, 1H), 4.80 (b, 1H), 3.94 (m, 1H), 3.87 (m,1H), 2.76 (s, 3H), 1.98-1.45 (m, 16H). MS m/z 459 (M+1).

EXAMPLE 29 Biological Activity

[0626] In the following example, “MEM” means Minimal Essential Media;“FBS” means Fetal Bovine Serum; “NP40” and “Igepal” are detergents;“MOI” means Multiplicity of Infection; “NaOH” means sodium hydroxide;“MgCl₂” means magnesium chloride; “dATP” means deoxyadenosine 5′triphosphate; “dUTP” means deoxyuridine 5′ triphosphate; “dCTP” meansdexoxycytidine 5′ triphosphate; “dGTP” means deoxyguanosine 5′triphosphate; “GuSCN” means Guanidinium thiocyanate; “EDTA” meansethylenediamine tetraacetic acid; “TE” means Tris-EDTA; “SCC” meanssodium chloride/sodium citrate; “APE” means a solution of ammoniaacetate, ammonia phosphate, EDTA; “PBS” means phosphate buffered saline;and “HRP” means horseradish peroxidase.

[0627] a) Tissue Culture and HSV Infection

[0628] Vero 76 cells were maintained in MEM with Earle's salts,L-glutamine, 8% FBS (Hyclone, A-1111-L) and 100 units/mL Penicillin-100μg/mL Streptomycin. For assay conditions, FBS was reduced to 2%. Cellsare seeded into 96-well tissue culture plates at a density of 5×10⁴cells/well after being incubated for 45 min at 37° C. in the presence ofHSV-1 or HSV-2 (MOI=0.001). Test compounds are added to the wells andthe plates are incubated at 37° C. for 40-48 hours. Cell lysates areprepared as follows: media was removed and replaced with 150 μL/well 0.2N NaOH with 1% Igepal CA 630 or NP-40. Plates were incubated up to 14days at room temperature in a humidified chamber to prevent evaporation.

[0629] (b) Preparation of Detection DNA.

[0630] For the detection probe, a gel-purified, digoxigenin-labeled,710-bp PCR fragment of the HSV UL-15 sequence was utilized. PCRconditions included 0.5 μM primers, 180 μM dTTP, 20 μM dUTP-digoxigenin(Boehringer Mannheim 1558706), 200 μM each of dATP, dCTP, and dGTP,1×PCR Buffer II (Perkin Elmer), 2.5 mM MgCl₂, 0.025 units/μL of AmpliTaqGold polymerase (Perkin Elmer), and 5 ng of gel-purified HSV DNA per 100μL Extension conditions were 10 min at 95° C., followed by 30 cycles of95° C. for 1 min, 55° C. for 30 sec, and 72° C. for 2 min. Theamplification was completed with a 10-min incubation at 72° C. Primerswere selected to amplify a 728 bp probe spanning a section of the HSV1UL15 open reading frame (nucleotides 249-977). Single-strandedtranscripts were purified with Promega M13 Wizard kits. The finalproduct was mixed 1:1 with a mixture of 6 M GuSCN, 100 mM EDTA and 200μg/mL herring sperm DNA and stored at 4° C.

[0631] (c) Preparation of Capture Plates.

[0632] The capture DNA plasmid (HSV UL13 region in pUC) was linearizedby cutting with Xba I, denatured for 15 min at 95° C. and dilutedimmediately into Reacti-Bind DNA Coating Solution (Pierce, 17250,diluted 1:1 with TE buffer, pH 8) at 1 ng/μL 75 μL/well were added toCorning (#3922 or 9690) white 96-well plates and incubated at roomtemperature for at least 4 hrs before washing twice with 300 μL/well0.2×SSC/0.05% Tween-20 (SSC/T buffer). The plates were then incubatedovernight at room temperature with 150 μL/well 0.2 N NaOH, 1% IGEPAL and10 μg/mL herring sperm DNA.

[0633] (d) Hybridization.

[0634] Twenty-seven (27) μL of cell lysate was combined with 45 μL ofhybridization solution (final concentration: 3M GuSCN, 50 mM EDTA, 100μg/ml salmon sperm DNA, 5×Denhardt's solution, 0.25×APE, and 5 ng of thedigoxigenin-labeled detection probe). APE is 1.5 M NH₄-acetate, 0.15 Mammonium phosphate monobasic, and 5 mM EDTA adjusted to pH 6.0. Mineraloil (50 μL) was added to prevent evaporation. The hybridization plateswere incubated at 95° C. for 10 minutes to denature the DNA, thenincubated at 42° C. overnight. The wells were washed 6× with 300 μL/wellSSC/T buffer then incubated with 75 μL/wellanti-digoxigenin-HRP-conjugated antibody (Boehringer Mannheim 1207733,1:5000 in TE) for 30 min at room temperature. The wells were washed 6×with 300 μL/well with PBS/0.05% Tween-20 before 75 μL/well SuperSignalLBA substrate (Pierce) was added. The plates were incubated at roomtemperature for 30 minutes and chemiluminescence was measured in aWallac Victor reader.

[0635] e) Results.

[0636] The following results were obtained for HSV-1. Example No. IC₅₀(μM) 1 1.5 3 0.6 4 3.1 6 0.4 8 0.8 9 23 10 33 11 1.6 12 36 13 3.3 17 2.918 1 19 0.7 20 0.5 21 0.5 22 0.2 23 0.8 24 5 25 0.5 26 1.4 27 0.5 28 1.7

[0637] The results demonstrate that the compounds of the presentinvention are useful for the treatment and prophylaxis of herpes viralinfections.

1. A compound of formula (I):

wherein: p is 0, 1, 2, 3 or 4; each R¹ is the same or different and isindependently selected from the group consisting of halo, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy,—OR¹⁰Ay, —OHet, —OR¹⁰Het, —C(O)R⁹, —C(O)Ay, —C(O)Het, —CO₂R⁹,—C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(O)NHR¹⁰Ay, —C(O)NHR¹⁰Het, —C(S)NR⁹R¹¹,—C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het,—S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay, —NHR¹⁰Het,—R¹⁰cycloalkyl, —R¹⁰Ay, —R¹⁰Het, —R¹⁰O—C(O)R⁹, —R¹⁰O—C(O)Ay,—R¹⁰O—C(O)Het, —R¹⁰O—S(O)_(n)R⁹, —R¹⁰OR⁹, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹,—R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(O)NR⁷Ay, —R¹⁰C(O)NHR¹⁰Het, —R¹⁰C(S)NR⁹R¹¹,—R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹, —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂NHCOR⁹, —R¹⁰NR⁷R⁸,—R¹⁰NR⁷Ay, —R¹⁰NHC(NH)NR⁹R¹¹, cyano, nitro and azido; or two adjacent R¹groups together with the carbon atoms to which they are bonded form acycloalkyl or a 5- or 6-membered heterocyclic group containing 1 or 2heteroatoms; each R⁷ and R⁸ are the same or different and areindependently selected from the group consisting of H, alkyl, alkenyl,cycloalkyl, cycloalkenyl, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁹R¹¹, —C(S)NR⁹R¹¹,—C(NH)NR⁹R¹¹, —SO₂R¹⁰, —SO₂NR⁹R¹¹, —R¹⁰cycloalkyl, —R¹⁰OR⁹, —R¹⁰C(O)R⁹,—R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R¹⁰,—R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂NHCOR⁹, —R¹⁰NR⁹R¹¹, —R¹⁰NHCOR⁹, —R¹⁰NHSO₂R⁹ and—R¹⁰NHC(NH)NR⁹R¹¹; each R⁹ and R¹¹ are the same or different and areindependently selected from the group consisting of H, alkyl,cycloalkyl, —R¹⁰cycloalkyl, —R¹⁰OH, —R¹⁰(OR¹⁰)_(w) wherein w is 1-10,and —R¹⁰NR¹⁰R¹⁰; each R¹⁰ is the same or different and is independentlyselected from the group consisting of alkyl, alkenyl, alkynyl,cycloalkyl and cycloalkenyl; Ay is aryl; Het is a 5- or 6-memberedheterocyclic or heteroaryl group; Y is N or CH; R² is selected from thegroup consisting of halo, alkyl, alkenyl, cycloalkyl, cycloalkenyl, Ay,Het, —OR⁷, —OAy, —OHet, —OR¹⁰Het, —S(O)_(n)R⁹, —S(O)_(n)Ay,—S(O)_(n)Het, —S(O)_(n)NR⁷R⁸, —NR⁷R⁸, —NHHet, —NHR¹⁰Ay —NHR¹⁰Het,—R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; n is 0, 1 or 2; R³ and R⁴ are the same ordifferent and are each independently selected from the group consistingof H, halo, alkyl, alkenyl, cycloalkyl, Ay, Het, —OR⁷, —OAy, —C(O)R⁷,C(O)Ay, —CO₂R⁷, —CO₂Ay, —SO₂NHR⁹, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Het,—R¹⁰cycloalkyl, —R¹⁰OR⁷, —R¹⁰OAy, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; Ring A is a5-10 membered heterocyclic or heteroaryl group; q is 0, 1, 2, 3, 4 or 5;and each R⁵ is the same or different and is independently selected fromthe group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OR¹⁰Ay, —OHet, —OR¹⁰Het, —C(O)R⁹,—C(O)Ay, —C(O)Het, —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(O)NHR¹⁰Het,—C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —S(O)_(n)R⁹, —S(O)₂NR⁷R⁸,—S(O)₂NR⁷Ay, —NR⁷R⁸, —NR⁷Ay, —NHHet, —NHR¹⁰Ay, —NHR¹⁰Het,—R¹⁰cycloalkyl, —R¹⁰Het, —R¹⁰OR⁹, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹,—R¹⁰C(O)NR⁷Ay, —R¹⁰C(O)NHR¹⁰Het, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹,—R¹⁰SO₂R⁹, —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂NHCOR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay,—R¹⁰NHC(NH)NR⁹R¹¹, cyano, nitro and azido; wherein when Y is CH, R³ isnot —NR⁷Ay; or a pharmaceutically acceptable salt, solvate orphysiologically functional derivative thereof.
 2. The compound accordingto claim 1 wherein p is 0, 1 or
 2. 3. The compound according to claim 1wherein p is
 1. 4. The compound according to claim 1 wherein each R¹ isthe same or different and is independently selected from the groupconsisting of halo, alkyl, Ay, Het, —OR⁷, —OAy, —C(O)Het, —CO₂R⁹,—C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(O)NHR¹⁰Het, —S(O)_(n)R⁹, —NR⁷R⁸, —NR⁷Ay,—NHHet, —NHR¹⁰Ay, —NHR¹⁰Het, —R¹⁰OR⁹, cyano, nitro and azido.
 5. Thecompound according to claim 1 wherein each R¹ is the same or differentand is independently selected from the group consisting of halo, alkyl,Het, —OR⁷, —C(O)NR⁷R⁸, —S(O)_(n)R⁹, —NR⁷R⁸, —NR⁷Ay and —NHHet.
 6. Thecompound according to claim 1 wherein R² is selected from the groupconsisting of Ay, Het, —OR⁷, —OHet, —OR¹⁰Het, —S(O)_(n)R⁹, —NR⁷R⁸,—NHHet, —NHR¹⁰Het and —R¹⁰NR⁷R⁸.
 7. The compound according to claim 1wherein R² is selected from the group consisting of —NR⁷R⁸ and Het. 8.The compound according to claim 1 wherein Y is N.
 9. The compoundaccording to claim 1 wherein Y is CH.
 10. The compound according toclaim 1 wherein R³ and R⁴ are the same or different and are eachindependently selected from the group consisting of H, halo, alkyl, Ay,—OR⁷, —CO₂R⁷, —NR⁷R⁸, —R¹⁰OR⁷ and —R¹⁰NR⁷R⁸.
 11. The compound accordingto claim 1 wherein R³ and R⁴ are each H.
 12. The compound according toclaim 1 wherein Ring A is selected from the group consisting of furan,pyridine, pyrimidine, thiazol, pyrazine, pyrrole, imidazole, oxazole,benzimidazole, quinoline, isoquinoline and quinoxoline.
 13. The compoundaccording to claim 1 wherein Ring A is selected from the groupconsisting of furan, thiazole, pyridine and pyrimidine.
 14. The compoundaccording to claim 1 wherein q is selected from the group consisting of0, 1 and
 2. 15. The compound according to claim 1 wherein q is
 1. 16.The compound according to claim 1 wherein each R⁵ is the same ordifferent and is independently selected from the group consisting ofhalo, alkyl, alkenyl, Ay, Het, —OR⁷, —OAy, —CO₂R⁹, —C(O)NR⁷R⁸,—C(O)NR⁷Ay, —S(O)₂NR⁷R⁸, —NR⁷R⁸, —NR⁷Ay, —NHR¹⁰Ay, cyano, nitro andazido.
 17. The compound according to claim 1, wherein each R⁵ is thesame or different and is independently selected from the groupconsisting of halo, alkyl, —OR⁷, —NR⁷R⁸, cyano, nitro and azido.
 18. Acompound selected from the group consisting of:N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-pyridinyl)pyrazolo[1,5-a]pyridin-7-amine;N-Cyclopentyl-3-[2-(methylamino)-4-pyrimidinyl]-2-(4-pyridinyl)pyrazolo[1,5-a]pyridin-7-amine;N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(3-pyridinyl)pyrazolo[1,5-a]pyridin-7-amine;N-Cyclopentyl-N-(4-{2-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-3-yl}-2-pyrimidinyl)amine;N-(4-{7-Chloro-2-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-3-yl}-2-pyrimidinyl)-N-cyclopentylamine;N-Cyclopentyl-2,3-bis[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine;N-(2-Methoxyethyl)-2,3-bis{2-[(2-methoxyethyl)amino]pyrimidin-4-yl}pyrazolo[1,5-a]pyridin-7-amine;N-Butyl-2,3-bis[2-(butylamino)pyrimidin-4-yl]pyrazolo[1,5-a]pyridin-7-amine;N-Cyclopropyl-2,3-bis[2-(cyclopropylamino)pyrimidin-4-yl]pyrazolo[1,5-a]pyridin-7-amine;7-Morpholin-4-yl-2,3-bis(2-morpholin-4-ylpyrimidin-4-yl)pyrazolo[1,5-a]pyridine;N-Isobutyl-2,3-bis[2-(isobutylamino)pyrimidin-4-yl]pyrazolo[1,5-a]pyridin-7-amine;N-Benzyl-2,3-bis[2-(benzylamino)pyrimidin-4-yl]pyrazolo[1,5-a]pyridin-7-amine;N-Isopropyl-2,3-bis[2-(isopropylamino)pyrimidin-4-yl]pyrazolo[1,5-a]pyridin-7-amine;2-(2-Fluoro-4-pyridinyl)-3-[2-(methylsulfanyl)-4-pyrimidinyl]pyrazolo[1,5-a]pyridine;4-[2-(2-Fluoro-4-pyridinyl)pyrazolo[1,5-a]pyridin-3-yl]-N-isopropyl-2-pyrimidinamine;N-Isopropyl-4-{2-[2-(isopropylamino)-4-pyridinyl]pyrazolo[1,5-a]pyridin-3-yl}-2-pyrimidinamine;3-[2-(Cyclopropylamino)-4-pyrimidinyl]-N-isopropyl-2-[2-(isopropylamino)-4-pyridinyl]pyrazolo[1,5-a]pyridin-7-amine;N-Cyclopentyl-2-[2-(cyclopentylamino)-4-pyridinyl]-3-[2-(isopropylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine;3-[2-(Cyclopentylamino)-4-pyrimidinyl]-N-isopropyl-2-[2-(isopropylamino)-4-pyridinyl]pyrazolo[1,5-a]pyridin-7-amine;N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-[2-(isopropylamino)-4-pyridinyl]pyrazolo[1,5-a]pyridin-7-amine;N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyridinyl]-2-(2-furyl)pyrazolo[1,5-a]pyridin-7-amine;N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(3-methyl-2-furyl)pyrazolo[1,5-a]pyridin-7-amine;N-Cyclopentyl-3-[2-(cyclopropylamino)-4-pyrimidinyl]-2-(3-methyl-2-furyl)pyrazolo[1,5-a]pyridin-7-amine;N-Cyclopropyl-3-[2-(cyclopropylamino)-4-pyrimidinyl]-2-(3-methyl-2-furyl)pyrazolo[1,5-a]pyridin-7-amine;N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(2-furyl)pyrazolo[1,5-a]pyridin-7-amine;3-[2-(Cyclopentylamino)-4-pyrimidinyl]-N-cyclopropyl-2-(2-furyl)pyrazolo[1,5-a]pyridin-7-amine;2-(5-Bromo-2-furyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine;andN-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyridinyl]-2-(2-methyl-1,3-thiazol-4-yl)pyrazolo[1,5-a]pyridin-7-amine;or a pharmaceutically acceptable salt, solvate or physiologicallyfunctional derivative thereof.
 19. A pharmaceutical compositioncomprising a compound according to claim
 1. 20. A pharmaceuticalcomposition according to claim 19 further comprising a pharmaceuticallyacceptable carrier or diluent.
 21. A pharmaceutical compositionaccording to claim 19 further comprising an antiviral agent selectedfrom the group consisting of aciclovir and valaciclovir.
 22. A methodfor the prophylaxis or treatment of a herpes viral infection in ananimal, said method comprising administering to the animal atherapeutically effective amount of a compound according to claim
 1. 23.The method according to claim 22, wherein said herpes viral infection isselected from the group consisting of herpes simplex virus 1, herpessimplex virus 2, cytomegalovirus, Epstein Barr Virus, varicella zostervirus, human herpes virus 6, human herpes virus 7 and human herpes virus8.
 24. A method for the prophylaxis or treatment of a condition ordisease associated with a herpes viral infection in an animal,comprising administering to the animal a therapeutically effectiveamount of a compound according to claim
 1. 25. A process for preparingthe compound according to claim 1 wherein Y is N and R³ and R⁴ are H;said process comprising reacting a compound of formula (IX):

with a compound of formula (X):


26. A process for preparing the compound according to claim 1, wherein Yis N; R³ is selected from the group consisting of of H, alkyl,cycloalkyl, alkenyl, Ay, Het, —OR⁷, —OAy, —C(O)R⁷, C(O)Ay, —CO₂R⁷,—CO₂Ay, —SO₂NHR⁹, —NR⁷R⁸ (where R⁷ and R⁸ are not H), —NR⁷Ay (where R⁷is not H), —R¹⁰cycloalkyl, —R¹⁰OR⁷, —R¹⁰OAy, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay;and R⁴ is H, said process comprising reacting a compound of formula(XVI):

with a compound of formula (X):


27. A process for preparing the compound according to claim 1 wherein Yis N, said process comprising reacting a compound of formula (XX):

with a compound of formula (X):

followed by oxidative aromatization.
 28. A process for preparing thecompound according to claim 1, said process comprising reacting acompound of formula (XXII):

wherein X¹ is chloro, bromo or iodo; with a compound of formula (XXIV):

wherein M² is selected from the group consisting of —B(OH)₂, —B(ORa)₂,—B(Ra)₂, —Sn(Ra)₃, Zn-halide, ZnRa, and Mg-halide, where Ra is alkyl orcycloalkyl and halide is halo.
 29. A process for preparing the compoundaccording to claim 1, said process comprising reacting a compound offormula (XXIX):

with a 1-aminopyridinium salt of formula (XXX):

wherein Z- is a counter ion.
 30. A process for preparing the compoundaccording to claim 1, said process comprising reacting a compound offormula (XXXVI):

with a suitable ring forming reagent.
 31. The process according to claim1 further comprising the step of converting a compound of formula (I) toa pharmaceutically acceptable salt, solvate or physiologicallyfunctional derivative thereof.
 32. The process according to claim 1further comprising the step of converting a compound of formula (I) or apharmaceutically acceptable salt, solvate or physiologically functionalderivative thereof to another compound of formula (I) or apharmaceutically acceptable salt, solvate or physiologically functionalderivative thereof. 33-38 (Canceled)